The lncRNA KIF9-AS1 Accelerates Hepatocellular Carcinoma Growth by Recruiting DNMT1 to Promote RAI2 DNA Methylation

Abstract

Background. Hepatocellular carcinoma (HCC) is a very common malignant tumor. Long noncoding RNAs (lncRNAs) enable discoveries of new therapeutic tumor targets. We aimed to study the role and potential regulatory mechanisms of the lncRNA KIF9-AS1 in HCC. Methods. CCK-8, scratch assay, and flow cytometry were used to detect cell proliferation, migration, and apoptosis, respectively. Bax, Bcl-2, ERK, and pERK expression were measured by western blotting. StarBase predicted KIF9-AS1 expression in HCC and paracancerous tissues. RPISeq predicted the interaction score of KIF9-AS1 and DNMT1, and MethyPrimer revealed the CpG island distribution in the RAI2 promoter. MSP was performed to measure RAI2 methylation. RIP and ChIP were performed to examine lncRNA KIF9-AS1, DNMT1, and RAI2 interactions. Finally, the effect of KIF9-AS1 knockdown on HCC was verified with nude mice. Results. We found that KIF9-AS1 expression was increased in HCC tissues. KIF9-AS1 knockdown inhibited the proliferation and migration, and facilitated the apoptosis of HCC cells. lncRNA KIF9-AS1-mediated RAI2 expression led to DNMT1 recruitment and regulated RAI2 DNA methylation. RAI2 overexpression inhibited the proliferation and migration and promoted the apoptosis of HCC cells. KIF9-AS1 knockdown inhibited subcutaneous tumor formation in vivo. Conclusion. This study shows that KIF9-AS1 accelerates HCC growth by inducing DNMT1 promotion of RAI2 DNA methylation.

Research Progress on the Role of Epigenetic Methylation Modification in Hepatocellular Carcinoma

“…96 Furthermore, RNAs can affect gene methylation or directly impact HCC by acting on the methylation level of the corresponding gene. [97][98][99][100] RNA methyltransferases (METTs) and RNA-binding proteins (RBPs) offer promising therapeutic targets in HCC. In m6A, METTL3 depends on the YTH domain family 2 (YTHDF2) of RBPs to regulate the proliferation, migration, and invasion of HCC cells.…”

“… 118 The formation of M1A is catalyzed by methyltransferases, with these “writers” specifically recognizing m1A sites as well as inducing downstream effects. 97 Genetic variations in m1A regulators may be linked to mutations in oncogenes, playing a role in the carcinogenesis or metabolic reprogramming of HCC. 90 While M1A regulates the PI3K/AKT/mTOR pathway in gastrointestinal cancers, its specific mechanisms in HCC remain to be fully elucidated.…”

Critical roles of lncRNA-mediated autophagy in urologic malignancies

“…Abnormal expression of lncRNA KIF9-AS1 has been reported in a variety of tumor cells and is closely associated with the progression of nasopharyngeal carcinoma ( You et al, 2020 ), hepatocellular carcinoma ( Yu et al, 2022 ), and ovarian cancer ( Li and Zhan, 2020 ). In Jin et al ’ s study, KIF9-AS1 was found to be highly expressed in renal cell carcinoma (RCC) tissue cells.…”