Epitranscriptic regulation of <i>HRAS</i> by <i>N</i>⁶-methyladenosine drives tumor progression.

Abstract

Overexpression of Ras, in addition to the oncogenic mutations, occurs in various human cancers. However, the mechanisms for epitranscriptic regulation of <i>RAS</i> in tumorigenesis remain unclear. Here, we report that the widespread <i>N</i>⁶-methyladenosine (m⁶A) modification of <i>HRAS</i>, but not <i>KRAS</i> and <i>NRAS</i>, 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 m⁶A modification sites of <i>HRAS</i> 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 <i>HRAS</i> m⁶A 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 m⁶A modification sites of <i>HRAS</i> and tumor progression, which provides a new strategy to target oncogenic Ras signaling.