HOXD9 contributes to the Warburg effect and tumor metastasis in non-small cell lung cancer via transcriptional activation of PFKFB3

Lung cancer is one of the most significant causes of cancer-related deaths, with non-small cell lung cancer (NSCLC) accounting for a large proportion [1]. Despite great progress in the early diagnosis and treatment of NSCLC, patient prognosis is still dismal, and the five-year survival rate is below 15% [2,3]. One pathology series has attributed a high metastasis rate as the primary cause of poor prognosis in patients with NSCLC, suggesting the occurrence of distant metastasis in more than half of the patients with newly diagnosed NSCLC [4]. Therefore, investigating the molecular mechanisms underlying NSCLC metastasis will help delineate efficient strategies for treating this lethal malignancy and improving patient outcomes.

Under both normoxic and hypoxic conditions, tumor cells prefer inefficient glycolysis to mitochondrial oxidative phosphorylation for glucose metabolism, a unique metabolic choice known as the Warburg effect. Increased glycolysis occurs in cells of numerous tumors, including NSCLC [5,6]. Previous studies have confirmed that the Warburg effect is greatly associated with distant metastasis in NSCLC [7,8]. The 6-phosphofructo-2-kinase (PFK2) isoform, PFKFB3, plays a key role in glycolysis by allosterically generating fructose-2,6-bisphosphate (F2,6P2) and activating 6-phosphofructo-1-kinase (PFK1) [9]. PFKFB3 has kinase activity that shunts glucose toward glycolysis and is overexpressed in many cancers [10]. Previous researches have shown the crucial carcinogenic role of PFKFB3 in the progression of NSCLC [11] and other types of tumors [12], with the mechanism possibly involving tumor cell glycolysis; however, the upstream regulatory mechanism of PFKFB3 remains unclear.

The HOX gene family is a highly conserved transcriptional gene family involved in many intracellular physiological processes, including intracellular signal transduction and apoptosis [13]. Recent studies have shown that the HOX gene family promotes tumor malignancy via activating or suppressing a diverse range of downstream target genes [14]. HOXD9, a member of the HOX family, is implicated in the development and advancement of certain cancers [15,16]. For instance, HOXD9 promotes the proliferation and survival of glioma cells [17], and is expressed at markedly higher levels in esophageal cancer than in neighboring tissues [18]. Moreover, ectopic HOXD9 simultaneously promoted HCC cell relocation, attack, and metastasis [19]. Notably, our results indicated that the mRNA level of the HOXD9 gene was substantially raised in the lung cancer tissues from the dataset of the Cancer Genome Atlas (TCGA) (Supplementary Fig. 1), suggesting that HOXD9 may be a potential signal molecule to modulate the occurrence and development of NSCLC. Nevertheless, the molecular mechanisms and the definitive role of HOXD9 in NSCLC is still unclear.

Here, our data revealed that HOXD9 is overexpressed in NSCLC tissues and facilitates the Warburg effect and tumor metastasis in NSCLC. Strikingly, HOXD9 directly binds to the PFKFB3 promoter region and promotes its transcription. PFKFB3 inhibition leads to the loss of HOXD9-mediated oncogenic effects in NSCLC. Our results showed that HOXD9 plays an oncogenic role in NSCLC and may offer a novel prospective therapeutic target for such deadly malignancies.

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