METTL3-mediated m6A modification of circCDYL promotes gastric cancer progression by acting as miR-378a-5p sponge to regulate USP13 expression.

Emerging evidence suggests that circular RNAs (circRNAs) play a crucial role in the occurrence and development of tumors. N6-methyladenosine (mA) is the most abundant type of RNA modification in eukaryotes. The regulatory effect of mA modification on circular RNA has not been fully understood. In this study, we found that circCDYL is highly expressed in human gastric cancer tissues. The increased expression of circCDYL is associated with the METTL3-medated mA modification of circCDYL at sites 471 and 500. The mA modification of circCDYL can be recognized and bound by mA "reader" protein YTHDC1. The interaction between YTHDC1 and the mA-modified circCDYL promotes the transport of circCDYL from the cell nucleus to the cytoplasm, thereby further increasing the generation of the circular RNA in the nucleus. Overexpression of circCDYL facilitates the cell cycle progression and accelerates the proliferation, invasion and migration of gastric cancer cells. In contrast, knockdown of circCDYL has opposite effects both in vitro and in vivo. Mechanistically, circCDYL can function as a molecular "sponge" for miR-378a-5p to regulate the expression of USP13, thereby promoting the progression of gastric cancer. Taken together, our current findings suggest that the METTL3-mediated mA modification of circCDYL promotes the progression of gastric cancer via the miR-378a-5p/USP13 axis. CircCDYL is expected to be a potential diagnostic biomarker and therapeutic target for gastric cancer.