Epitranscriptic regulation of HRAS by N 6 -methyladenosine drives tumor progression

Overexpression of Ras, in addition to the oncogenic mutations, occurs in various human cancers. However, the mechanisms for epitranscriptic regulation of in tumorigenesis remain unclear. Here, we report that the widespread -methyladenosine (m A) modification of , but not and , is higher in cancer ti...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (14), p.e2302291120
Main Authors: Pan, Yongbo, Gu, Yinmin, Liu, Tihui, Zhang, Qingqing, Yang, Facai, Duan, Liqiang, Cheng, Shuwen, Zhu, Xiaofeng, Xi, Yibo, Chang, Xiaoli, Ye, Qinong, Gao, Shan
Format: Article
Language:English
Subjects:
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
Carcinogenesis
Cell Transformation, Neoplastic - genetics
Humans
Neoplasms - genetics
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Transcription, Genetic
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Summary:Overexpression of Ras, in addition to the oncogenic mutations, occurs in various human cancers. However, the mechanisms for epitranscriptic regulation of in tumorigenesis remain unclear. Here, we report that the widespread -methyladenosine (m A) modification of , but not and , is higher in cancer tissues compared with the adjacent tissues, which results in the increased expression of H-Ras protein, thus promoting cancer cell proliferation and metastasis. Mechanistically, three m A modification sites of 3' UTR, which is regulated by FTO and bound by YTHDF1, but not YTHDF2 nor YTHDF3, promote its protein expression by the enhanced translational elongation. In addition, targeting m A modification decreases cancer proliferation and metastasis. Clinically, up-regulated H-Ras expression correlates with down-regulated FTO and up-regulated YTHDF1 expression in various cancers. Collectively, our study reveals a linking between specific m A modification sites of and tumor progression, which provides a new strategy to target oncogenic Ras signaling.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2302291120