Research ArticleOncology Open Access | 10.1172/JCI175949

Baotong Zhang,1,2,3 Mingcheng Liu,1 Fengyi Mai,1 Xiawei Li,1,4 Wenzhou Wang,1 Qingqing Huang,1 Xiancai Du,1 Weijian Ding,1 Yixiang Li,2,3 Benjamin G. Barwick,2,3 Jianping Jenny Ni,2,3 Adeboye O. Osunkoya,3,5 Yuanli Chen,6 Wei Zhou,2,3 Siyuan Xia,1,2,3 and Jin-Tang Dong1,2,3

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

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1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Du, X. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Ding, W. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Li, Y. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Barwick, B. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Ni, J. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Osunkoya, A. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Chen, Y. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Zhou, W. in: JCI | PubMed | Google Scholar |

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Xia, S. in: JCI | PubMed | Google Scholar

1Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

4Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China.

5Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

6Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.

Address correspondence to: Baotong Zhang, Southern University of Science and Technology, Huiyuan Building 5, Room 303, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88010102; Email: zhangbt@sustech.edu.cn. Or to: Jin-Tang Dong, Southern University of Science and Technology, Research Building B, Room 508, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong 518055, China. Phone: 86.0755.88018032; Email: dongjt@sustech.edu.cn.

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Find articles by Dong, J. in: JCI | PubMed | Google Scholar

Authorship note: BZ, ML, and FM are co–first authors and contributed equally to this work.

Published May 23, 2024 - More info

Published in Volume 134, Issue 14 on July 15, 2024
J Clin Invest. 2024;134(14):e175949. https://doi.org/10.1172/JCI175949.
© 2024 Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published May 23, 2024 - Version history
Received: September 19, 2023; Accepted: May 21, 2024 View PDF Abstract

Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1.

Graphical Abstract Introduction

Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States (1). Most prostate cancers are localized and androgen dependent at diagnosis and can thus be effectively treated with chemical castration, surgery, and radiation (2). Approximately 12% of prostate cancers progress to metastatic castration-resistant prostate cancer (mCRPC) (3), which contributes to mortality. Genetic drivers of prostate cancer have been extensively studied and defined to categorize disease subtypes and develop subtype-specific therapeutic strategies. One of the most potent genetic drivers of prostate cancer is phosphatase and tensin homolog (PTEN), a tumor suppressor gene that is mutated in approximately 20% of primary prostate cancers and in up to 50% of patients with mCRPC (4, 5).

PTEN inactivation results in prostate intraepithelial neoplasia (PIN) by activating PI3K/AKT signaling in genetically engineered mouse models, in which prostate cancer has a long latency to progress to high-grade adenocarcinoma, with metastasis occurring rarely (6–8). The limited tumor progression induced by PTEN deficiency suggests that additional molecular and cellular responses are activated to constrain tumor progression. In line with the higher frequency of PTEN mutations in patients with mCRPC, PTEN inactivation also co-occurs with other mutations in advanced prostate cancer (9). More directly, loss of p53 or Smad4 largely enhances the progression of prostate cancer and contributes to metastatic prostate cancer by overcoming senescence-induced by Pten deletion (7, 10). Activation of kinase pathways such as RAS/MAPK or HER2 also promotes tumor progression of PTEN-deficient prostate cancer (11, 12). On the other hand, tumor progression is not a monologue but rather an interplay with the surrounding cells in the tumor microenvironment (TME). It remains elusive whether and how TME remodeling is required for PTEN-deficient prostate cancer to overcome the progression barriers. Understanding these second hits for the progression of PTEN-deficient prostate cancer will provide a rationale for combined therapeutic strategies in the treatment of prostate cancer.

TGF-β signaling is prominent in PTEN-deficient prostate cancer tumors in addition to PI3K and p53 signaling (10). TGF-β/BMP-SMAD4 signaling is robustly activated in PTEN-null prostate cancers (10). Knockout of Smad4, a key component of the TGF-β pathway, results in invasive, metastatic, and lethal prostate cancers with 100% penetrance (10). TGF-β is produced by both cancer cells and the TME and actively reshapes the TME (13). While TGF-β inhibits tumor growth in early-stage tumors, it induces epithelial-mesenchymal transition (EMT) and promotes cancer metastasis in later-stage tumors (14–19).

Acetylation of the transcription factor Krüppel-like factor 5 (KLF5) at lysine 369 (K369) has been identified as a posttranscriptional modification downstream of TGF-β. KLF5 acetylation is induced by TGF-β via the SMAD-recruited p300 acetylase (20, 21). Acetylated KLF5 (Ac-KLF5) then forms a transcriptional complex, distinct from that of deacetylated KLF5 (deAc-KLF5), which is essential for TGF-β to function in gene regulation, cell proliferation, and tumorigenesis (20–23). However, it remains unclear whether and how KLF5 acetylation remodels the TME in prostate cancer progression. In our most recent study, we found that Ac-Klf5 is essential for proper basal-to-luminal differentiation in the prostate and that loss of Klf5 acetylation in basal progenitor cells results in low-grade PIN (24), suggesting a role of Klf5 acetylation in prostate cancer progression. More important, we established a genetically engineered mouse model (GEMM) to conditionally interrupt Klf5 acetylation, providing a unique animal model to address the role of Ac-KLF5 in the progression of PTEN-deficient prostate cancer (24).

Here, we found that Klf5 acetylation at K358 (a homologous site of human KLF5 K369) was significantly (P < 0.001) increased by Pten loss in mouse prostates and phosphorylated AKT (p-AKT) activation in human prostates. Interruption of Klf5 acetylation promoted tumor growth in Pten-deficient prostate cancer, as indicated by larger tumor sizes and enhanced cell proliferation. Mechanistically, the KLF5 acetylation–dependent barrier induced by PTEN deficiency constrained prostate tumor growth by attenuating FGF receptor 1 (FGFR1) signaling. Deacetylation of KLF5 in prostate cancer cells stimulated inflammatory cancer-associated fibroblasts (iCAFs) through TNF-α to release FGF9, which in turn activated FGFR1 signaling in prostate cancer cells. In addition to the paracrine signaling, deAc-KLF5 induced CX3CR1, which was required by FGF9 to activate FGF receptor 1 (FGFR1) signaling. Inhibition of CX3CR1 sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study not only clarifies the role of KLF5 acetylation in reciprocal communications between prostate cancer cells and iCAFs in PTEN-deficient tumors, but also provides a proof of concept for posttranslational modifications (PTMs) as essential molecular events induced by PTEN inactivation to stall prostate cancer progression.

Results

PTEN deficiency induces KLF5 acetylation in mouse and human prostate tumors. KLF5 acetylation at K369 is induced by TGF-β and has been identified as a crucial PTM downstream of TGF-β in mediating TGF-β’s functions (20, 21). Given the robust activation of TGF-β in PTEN-deficient prostate cancer, we tested whether KLF5 acetylation at K369 is affected by PTEN/PI3K/p-AKT signaling. Prostate-specific Pten knockout led to adenocarcinoma in mouse prostate (6) and induced Klf5 acetylation at K358 (a homologous site of human KLF5 K369 Figure 1, A and B), as indicated by IHC staining. Knockin of the Klf5K358R (Klf5KR) mutant in Pten-null mouse prostate successfully depleted Klf5 acetylation, validating the induction of Klf5 acetylation at K358 by Pten knockout (Figure 1, A and B).

Figure 1

PTEN loss induces KLF5 acetylation in mouse and human prostates. (A and B) IHC staining of acetylated Klf5 at K358 in 4-month-old mice with the indicated genotypes, as shown in the representative images (A) and statistical analysis (B). ***P < 0.001, by 2-way ANOVA. (C and D) IHC staining of acetylated KLF5 at K369 in human prostate cancer specimens with or without AKT activation, as indicated by the representative images (C) and statistical analysis (D). Scale bars: 50 μm (A and C). Data are shown as the mean ± SEM. ***P < 0.001, by 2-tailed Student’s t test.

PTEN loss activated PI3K/AKT signaling to promote prostate cancer progression. In human prostate cancer samples, we found that Ac-KLF5 expression was significantly higher when AKT was activated (Figure 1, C and D), consistent with the findings in the GEMM. We also evaluated the expression levels of total KLF5 in both GEMM and human prostate cancer specimens but did not observe significant differences in tissues with or without AKT activation (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/JCI175949DS1).

Interruption of Klf5 acetylation by the K358R mutation promotes Pten-null prostate tumor growth. Knockin of the Klf5KR mutant successfully interrupted Klf5 acetylation in Pten-deficient mouse prostates (Figure 1, A and B), providing an ideal model with which to test how Klf5 acetylation affects Pten-deficient prostate cancer. Klf5KR knockin led to larger tumors in Pten-deficient prostates of 6-month-old mice, as indicated by the tumor images and prostate weights (Figure 2, A and B). In addition, knockin of 1 allele of Klf5KR appeared to efficiently enlarge tumor sizes within 6 months, although the increase in tumor sizes did not reach significance at 1 to approximately 1.5 years, probably due to the considerable variations among prostate weights (Figure 2B). Further pathological evaluation indicated that knockin of Klf5KR resulted in more proliferative cells in prostate tumors, as suggested by both the mitotic images and frequency of Ki67+ cells (Figure 2, C–E), but did not significantly altered the expression patterns of epithelial markers, such as Ar, Ck5, and Ck8 (Supplemental Figure 1C). Mouse prostate cancer cells were used for organoid formation assays (Figure 2, F and G). Klf5KR knockin gave rise to more and larger organoids, indicating a role of deAc-KLF5 in promoting prostate tumor growth. One allele of Klf5KR knockin appeared insufficient to promote organoid formation (Figure 2, F and G), implying that the extent of Klf5 acetylation may be an essential factor in suppressing tumor growth. Collectively, interruption of Klf5 acetylation at K358 promoted prostatic tumor growth by accelerating cell proliferation.

Figure 2

Deacetylation of Klf5 accelerates cell proliferation and the growth of tumors induced by Pten loss in the prostate. (A and B) Knockin of Klf5K358R (Klf5KR) increased the weight of Pten-deficient mouse prostates, as indicated by the tumor images (A) and tumor weights (B). (C–E) Histological features of 16-week mouse prostates revealed by H&E staining (C) and proliferation index detected by Ki67 IHC staining (D and E). (F and G) Organoid culture of prostate epithelial cells with the indicated genotypes, as indicated by representative organoid images (F) and statistical analysis of organoid numbers (G). Scale bars: 50 μm. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (B and G) and 2-way ANOVA (E).

Deacetylation of KLF5 causes hyperactivated FGFR1 signaling in PTEN-deficient tumors. To understand the underlying mechanisms by which deacetylation of Klf5 promotes Pten-deficient prostate cancer progression, we performed RNA-Seq to identify differentially expressed genes (DEGs) in Pten-null mouse prostates with or without Klf5KR knockin. Anterior and dorsal prostates were dissected for RNA-Seq separately to capture gene expression (Figure 3A and Supplemental Data Sets 1 and 2). In anterior prostates (APs), Klf5KR knockin induced the expression of 31 genes and suppressed the expression of 162 genes (fold change >2 and P < 0.01). In dorsal prostates (DPs), Klf5KR knockin induced the expression of 107 genes and suppressed the expression of 80 genes (fold change >2 and P < 0.01). Functional annotations of differential gene expression by Gene Ontology (GO) analysis revealed the top 20 significant (adjusted P < 0.05) biological processes in both APs and DPs (Supplemental Figure 2, A and B). Notably, genes regulating cell-cell adhesion were enriched in both APs and DPs (Supplemental Figure 2, A and B). Further investigation of the genes associated with the top enriched biological processes suggested that Klf5KR knockin enriched several genes involved in cell-cell communications, specifically some cytokines and cytokine receptors (Supplemental Figure 2C). Given that Smad4 is induced by Pten knockout and constrains tumor progression (10), we compared the DEGs after Klf5KR knockin with those caused by Smad4 knockout. The genes that are upregulated by Smad4 knockout were enriched in Klf5KR-knockin–upregulated genes, and the Smad4-knockout–downregulated genes were enriched in Klf5KR-knockin–suppressed genes (Supplemental Figure 2D). These findings suggest that Klf5 acetylation is a barrier for Pten-null prostate cancer progression, just like Smad4 (10).

Figure 3

Interruption of Klf5 acetylation enhances FGFR1 signaling in Pten-deficient prostate tumors. (A) Differential gene expression caused by Klf5K358R (KR) knockin in Pten-loss mouse prostates, as determined by RNA-Seq in APs and dorsal DPs. (B) GSEA of RNA-Seq data on prostates from 16-week-old PBCre Pten–/– Klf5KR/KR (KR) and PBCre Pten–/– Klf5+/+ (WT) mice from 124 prostate-associated data sets. (C) GSEA using the gene sets containing FGFR1 upregulated and downregulated genes from Acevedo et al. (42). (D) Knockin of Klf5KR enhances the activation of Erk, Akt, and Frs2, as detected by IHC staining for p-ErkThr202/Tyr204, p-AktSer473, and p-Frs2Tyr436. Scale bars: 50 μm. MSI, mean staining intensity. Data are shown as the mean ± SEM. ***P < 0.001, by 2-way ANOVA.

Focusing on the gene profiles altered by the interruption of Klf5 acetylation, we further performed gene set enrichment analysis (GSEA) using a gene set library containing 124 prostate-associated gene sets from the Molecular Signatures Database (MSigDB). Interestingly, FGFR1-regulated gene sets were among the top enriched sets in both AP and DP (Figure 3B). FGFR1-induced genes were significantly enriched among Klf5KR-knockin–upregulated genes, and FGFR1-downregulated genes were significantly enriched in Klf5KR-knockin–suppressed genes (Figure 3C). The enrichment was significant in both AP and DP (Figure 3C). These GSEA data clearly indicate that interruption of Klf5 acetylation at K358 further enhanced FGFR1 signaling in Pten-deficient prostate tumors.

We also confirmed the activation of Fgfr1 signaling in Pten-deficient mouse prostates with Klf5KR knockin by detecting p-Frs2, p-Erk, and p-Akt, the canonical downstream signals of Fgfr1 (25). As expected, interruption of Klf5 acetylation at K358 significantly induced the activation of Frs2, Erk, and Akt (Figure 3D), indicating that the acetylation of Klf5 at K358 constrained Fgfr1 activation in Pten-knockout mouse prostates. The activation of Fgfr1 by Klf5KR knockin was also confirmed by Western blotting (Supplemental Figure 1D), and consistent results were achieved.

Single-cell RNA-Seq reveals enhanced FGF signaling from fibroblasts to cancer cells. To investigate whether and how TME signaling is attributed to FGFR1 overactivation, we performed single-cell RNA-Seq (scRNA-Seq) to analyze the crosstalk between prostate cancer cells and other types of cells in the microenvironment. We profiled 61,713 individual cells from fresh, dissociated whole prostates of four 16-week-old PBCre Pten–/– mice after quality control. These cells included 14,464 and 18,024 cells from two Klf5WT (WT) mice, and 12,310 and 16,915 cells from two Klf5KR (KR) mice. Clustering analysis identified 10 distinct clusters of 820 to 26,543 cells each (Figure 4A