ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

Abstract

Abstract Zinc-finger homeobox 3 (ZFHX3, also known as ATBF1) suppresses prostatic tumorigenesis; ZFHX3 is frequently found to have numerous deletions when found in human prostate cancer (PCa). However, the underlying molecular function of ZFHX3 during prostatic tumorigenesis is not well understood. N6-methyladenosine (m6A) modification in RNA plays a critical role in the development of cancers; however, the relationship between ZFHX3 and m6A modification is largely unknown in PCa. In this study, we found that ZFHX3 knockdown decreased total m6A levels through enhancing the transcriptional activity of FTO in PCa cells. Importantly, FTO inhibition suppressed cell proliferation and rescued the promoting function of ZFHX3 knockdown on cell proliferation. Through transcriptome sequencing and Me-RIP sequencing, we revealed that E2F2 and CDKN2C were the direct targets of FTO-mediated m6A modification and identified the role of E2F2 and CDKN2C in cell cycle arrest in FTO-depleted cells. Interestingly, ZFHX3 expression was in return regulated by FTO in m6A-dependent way. In vivo, we verified that FTO was upregulated and ZFHX3 was decreased in PCa patients and that a high level of ZFHX3 is indispensable for low FTO expression and is correlated with better patient survival. These findings establish a novel crosstalk mechanism between ZFHX3 and FTO in prostatic tumorigenesis.