Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification in mammalian mRNAs. Despite its functional importance in various physiological events, the role of m6A in chemical carcinogenesis remains largely unknown. Here we profiled the dynamic m6A mRNA modification during cellular transformation induced by chemical carcinogens and identified a subset of cell transformation-related, concordantly modulated m6A sites. Notably, the increased m6A in 3′-UTR mRNA of oncogene CDCP1 was found in malignant transformed cells. Mechanistically, the m6A methyltransferase METTL3 and demethylases ALKBH5 mediate the m6A modification in 3′-UTR of CDCP1 mRNA. METTL3 and m6A reader YTHDF1 preferentially recognize m6A residues on CPCP1 3′-UTR and promote CDCP1 translation. We further showed that METTL3 and CDCP1 are upregulated in the bladder cancer patient samples and the expression of METTL3 and CDCP1 is correlated with the progression status of the bladder cancers. Inhibition of the METTL3-m6A-CDCP1 axis resulted in decreased growth and progression of chemical-transformed cells and bladder cancer cells. Most importantly, METTL3-m6A-CDCP1 axis has synergistic effect with chemical carcinogens in promoting malignant transformation of uroepithelial cells and bladder cancer tumorigenesis in vitro and in vivo. Taken together, our results identify dynamic m6A modification in chemical-induced malignant transformation and provide insight into critical roles of the METTL3-m6A-CDCP1 axis in chemical carcinogenesis.

Multiple Functions and Mechanisms Underlying the Role of METTL3 in Human Cancers

“…In addition, METTL3-mediated m 6 A modification can directly regulate the transcription and translation of oncogenes and tumor suppressors coupled to the most of the important pathways involved in cancer cell progression, such as the PI3K/AKT (36,44,47,57,60,62), wnt/βcatenin (46), and P38/ERK (26) pathways. METTL3 can also regulate cancer-related gene expression via m 6 A modification (30,42,66,67). In conclusion, METTL3-related m 6 A regulatory genes involve multiple pathways and the opposing role of METTL3 in different cancer types may be associated with genes with opposing function, some of which we currently do not know.…”

“…Recent studies noted that METTL3 was drastically upregulated in bladder cancer tissues and was related to tumor histological grade. Patients with high expression of METTL3 had poor prognosis and reduced survival time (28)(29)(30). Knockdown of METTL3 significantly reduced bladder cancer cell invasion, proliferation, and survival in vitro and tumorigenicity in vivo (31).…”

“…METTL3 can regulate tumor cell progression by modulating the expression of oncogenes such as CUB domain-containing protein 1 (CDCP1)(30), integrin subunit alpha 6 (ITGA6) (66), and mammalian HBXIP(42) or tumor suppressors [such as P53 (67)] in an m 6 A-dependent manner. Miao et al demonstrated that METTL3 silencing decreased the expression of lymphoid enhancer-binding factor 1 (LEF1) because knockdown of METTL3 reduced the m 6 A level and shortened the half-life of LEF1 mRNA transcripts and subsequently inhibited the wnt/βcatenin pathway in human osteosarcoma(46).…”

m6A-binding proteins: the emerging crucial performers in epigenetics

“…Knockdown of YTHDF1 and YTHDF3 abrogated the expression of ITGA6. Another study showed that BC-related oncogene CPCP1 could be marked by m 6 A and selectively recognized by YTHDF1 [60]. And YTHDF1 remarkably increased CDCP1 expression.…”

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

“…Subsequently, mature miR221/222 restrains the expression of the antioncogene PTEN and ultimately boosts tumor growth both in vitro and in vivo. Based on the preferential m 6 A recognition by YTHDF1, METTL3 also facilitates translation of oncogene CDCP1, which plays a pivotal role in bladder cancer progression (47). Simultaneously, this biological process exerts synergistic effect with chemical carcinogens in malignant transformation of uroepithelial cells.…”