RNA m6a Methylation Regulator Expression in Castration-Resistant Prostate Cancer Progression and Its Genetic Associations

Abstract

N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature predominantly addresses m6A regulators in the context of primary prostate cancer (PCa). However, a notable gap in the knowledge emerges regarding the dynamic expression patterns of these regulators as PCa progresses towards the castration-resistant stage (CRPC). Employing sequential window acquisition of all theoretical mass spectra (SWATH-MS) and RNAseq analysis, we comprehensively profiled the expression of 27 m6A regulators in hormone/androgen-dependent and -independent PCa cell lines, revealing distinct clustering between tumor and adjacent normal prostate tissues. High-grade PCa tumors demonstrated the upregulation of METTL3, RBM15B, and HNRNAPA2B1 and the downregulation of ZC3H13, NUDT21, and FTO. Notably, we identified six m6A regulators associated with PCa survival. Additionally, association analysis of the PCa-associated risk loci in the cancer genome atlas program (TCGA) data unveiled genetic variations near the WTAP, HNRNPA2B1, and FTO genes as significant expression quantitative trait loci. In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis.

Systematic Multi-Omics Investigation of Androgen Receptor Driven Gene Expression and Epigenetics changes in Prostate Cancer

“…For example, RNA sequencing (RNAseq) provides comprehensive insights into gene expression profiles, enabling the identification of key genes and pathways involved in prostate cancer progression and treatment response. RNAseq has been instrumental in characterizing gene expression changes in prostate cancer cell lines under various conditions, such as androgen/anti-androgen treatment 29 . The Assay for Transposase-Accessible Chromatin using sequencing (ATACseq) allows researchers to investigate chromatin accessibility, providing insights into open chromatin regions and transcription factor binding sites 30 .…”