RBM15 promotes hepatocellular carcinoma progression by regulating N6-methyladenosine modification of YES1 mRNA in an IGF2BP1-dependent manner

Abstract

The function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1–YES1–MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.

The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer

“…In hepatocellular carcinoma (HCC), ALKBH5, an m 6 A demethylase, inhibits LY6/PLAUR Domain Containing 1 (LYPD1) that is recognized and then stabilized by IGF2BP1 142 . In HCC, RNA-binding motif protein 15 (RBM15) facilitates cancer progression via promoting post-transcriptional activation of YES1 in IGF2BP1-mediated m 6 A manner 143 . In addition, ALKBH5 also blocks pancreatic cancer progression through activation of PER1 by another m 6 A reader, YTHDF2 82 .…”

Construction of a Necroptosis-Related miRNA Signature for Predicting the Prognosis of Patients With Hepatocellular Carcinoma

“…Meanwhile, Yassin et al (2022 ) explored silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis, and hepatocellular carcinoma growth via modulation of the TNF signaling pathway. In addition, activation of the cAMP signaling pathway in HCC also appeared to be associated with epigenetic modifications, as in Cai et al’s (2021 ) study that RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1-YES1-MAPK axis. This seems to suggest that there is cross-talk in the pathways that promote the development of HCC.…”

Identification of CFHR4 as a Potential Prognosis Biomarker Associated With lmmune Infiltrates in Hepatocellular Carcinoma

“…We also observed significant correlations between high CFHR4 expression and YTHDC1, IGF2BP1, IGF2BP2, IGF2BP3, YTHDF1, YTHDF2, HNRNPA2B1, LRPPRC, HNRNPC, RBMX, METTL16, METTL3, RBM15, RBM15B, VIRMA, WTAP and ALKBH5 expression. Multiple studies have now reported that IGF2BP1 ( 62 ), IGF2BP2 ( 28 ), IGF2BP3 ( 63 ), YTHDF1 ( 64 ), YTHDF2 ( 29 ), BRMX ( 65 ), RBM15 ( 66 ), METTL3 ( 67 ) and WTAP ( 27 ) are significantly upregulated in HCC, and their overexpression promotes HCC progression and is associated with a poor prognosis for patients with HCC. These discussions further supported our results.…”