The role of SAM-dependent internal m7G modification of LINC01252 in the progression of hepatocellular carcinoma

Abstract Dysregulation of long non-coding RNAs (lncRNAs) plays a significant role in the progression of hepatocellular carcinoma (HCC), yet many underlying mechanisms remain elusive. Recent studies have highlighted the critical importance of internal N 7 -methylguanosine (m 7 G) modifications in influencing RNA expression and function. In this study, we identified LINC01252, a poorly characterized lncRNA, through analyses of GEO datasets and the TCGA cohort. Notably, LINC01252 is downregulated in HCC tissues and is associated with prognostic outcomes, although the predictive value of a nomogram based on LINC01252 expression characteristics appears to be limited. Our results indicate that LINC01252 effectively inhibits tumorigenic behaviors in HCC and exerts its effects by targeting the oncogene NUPR1. Mechanistically, LINC01252 acts as an intranuclear lncRNA that binds to the NUPR1 promoter through Hoogsteen pairing, consequently inhibiting its transcriptional activity. Additionally, the internal m 7 G modification level of LINC01252 directly influences its RNA stability, contingent upon sufficient concentrations of S-adenosylmethionine (SAM), which is necessary for the activity of its key modifying enzymes, METTL1 and WDR4. Thus, LINC01252’s m 7 G modification and expression are SAM-dependent in the context of HCC. Furthermore, LINC01252 can also suppress WDR4 transcription by binding to its promoter through the same mechanism, thus inhibiting HCC progression. Our findings suggest that LINC01252 functions as a SAM-dependent, m 7 G-related lncRNA, acting as a transcriptional repressor of NUPR1 and WDR4, while establishing a negative feedback loop between LINC01252 and WDR4. However, the potential of LINC01252 as a clinical biomarker still requires further investigation.