Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma

Gliomas are the most common primary tumors in the nervous system and have the strongest aggressive ability, contributing to approximately 80% of all cerebral tumors (Molinaro et al., 2019). The main cancer treatment regimen, including surgical excision, radiotherapy, and chemotherapy, provides negligible desirable therapeutic effects, resulting in poor prognosis and a high rate of fatalities (Lim et al., 2018; Siegelin et al., 2021). Extensive studies have proven that many molecules are involved in the invasion and proliferation of glioma cells. However, only a few molecular mechanisms have been revealed and applied in the clinic (Nagaraja et al., 2017; Phillips et al., 2020). Hence, it is urgent to explore new and effective strategies as well as underlying therapeutic targets for glioma therapy.

Long-read RNA sequencing technologies, such as Nanopore sequencing and single-molecule real-time (SMRT) long-read isoform sequencing (Iso-Seq), are attractive methods to understand gene expression profiling (Bayega et al., 2018). These methods show various unique advantages, contributing to comprehensively identifying full-length splice variants and other RNA events (Zhao et al., 2019). In cancer, long-read RNA sequencing has been conducted in multiple cancer types, such as hepatocellular carcinoma (Chen et al., 2019) and non-small cell lung cancer (Oka et al., 2021). Similarly, the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-Seq), a method for assessing genome-wide chromatin accessibility, has been applied to interrogate DNA accessibility in tumor progression, such as pancreatic cancer (Dhara et al., 2021), gastric cancer (Shin et al., 2021), and breast cancer (Shu et al., 2020). In glioma, the application of ATAC-Seq, extrachromosomal circular DNA (Kumar et al., 2020), and chromatin accessibility (Tome-Garcia et al., 2018; Wang et al., 2019; Narayanan et al., 2020) have been scrutinized in multiple studies. Combined long-read RNA sequencing and ATAC-seq in glioma remained unreported.

Abnormal RNA molecular events, novel transcripts (NT), alternative splicing (AS) events, gene fusion (GF) transcripts, and alternative polyadenylation (APA) generated by somatic and germline mutation, coding, and noncoding mutation are common cancer traits (Rheinbay et al., 2020), including glioma (Correa et al., 2016; Wang, L.B. et al., 2021). Masamha CP et al. reported a pivotal role of CFIm25 in governing alternative polyadenylation (APA) and demonstrated the connection between CFIm25 and glioblastoma tumorigenicity (Masamha et al., 2014). Bao ZS et al. uncovered a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastoma (Bao et al., 2014). Splicing factors such as SRSF1 and SRSF3 were identified as significant onco-drivers in glioma genesis (Zhou et al., 2019; Fuentes-Fayos et al., 2020). The identification of novel glioma-related RNA molecular events would potentially further clarify glioma pathogenesis.

FAM20C, along with FAM20A and FAM20B, is a secretory protein that regulates a variety of networks in secretory pathways (Palma-Lara et al., 2021). FAM20C is the archetypical member of the FAM20 family, and it is mainly responsible for the kinase of mineralization. However, it is also ubiquitously expressed. Therefore, accumulating evidence suggests that FAM20C is broadly correlated with a panel of cancers, including breast cancer, bladder cancer, and colorectal cancer (Xu et al., 2021). Recently, there was one report about FAM20C in glioma (Feng et al., 2021). They utilized the TCGA database, and their analysis was based on mRNA-seq data. Little information is known about the epigenetics of FAM20C and the translation of FAM20C. Herein, in our study, long-read Nanopore RNA sequencing was first conducted in 3 paired glioma and adjacent normal samples (discovery group) and then validated the identified RNA events of NT, AS, GF, APA, and differentially expressed transcripts (DETs) or genes (DEGs) in another 6 paired glioma and adjacent normal samples (validation group). The regulatory effects of chromatin accessibility and APA events on gene expression were analyzed, and two genes with clinical significance, functions, and transcriptional regulators were investigated.

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