Mechanisms underlying hepatocellular carcinoma progression through N6-methyladenosine modifications of long non-coding RNA

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited treatment options, particularly for patients with advanced stages of the disease. Sorafenib, the standard first-line therapy, faces significant challenges due to the development of drug resistance. Yu et al explored the mechanisms by which lncRNA KIF9-AS1 regulates the stemness and sorafenib resistance in HCC using a combination of cell culture, transfection, RNA immunoprecipitation, co-immunoprecipitation, and xenograft tumor models. They demonstrate that N6-methyladenosine-modified long non-coding RNA KIF9-AS1 acts as an oncogene in HCC. This modification involves methyltransferase-like 3 and insulin-like growth factor 2 mRNA-binding protein 1, which play critical roles in regulating KIF9-AS1. Furthermore, KIF9-AS1 stabilizes and upregulates short stature homeobox 2 by promoting its deubiquitination through ubiquitin-specific peptidase 1, thereby enhancing stemness and contributing to sorafenib resistance in HCC cells. These findings provide a theoretical basis for KIF9-AS1 as a diagnostic marker and therapeutic target for HCC, highlighting the need for further investigation into its clinical application potential.

Keywords: Hepatocellular carcinoma; Long non-coding RNA KIF9-AS1; N6-methyladenosine; Short stature homeobox 2; Sorafenib resistance; Stemness.