SNHG6 Promotes Lipid Metabolic Reprogramming in Hepatocellular Carcinoma via Upregulation of SCD.

Abstract

Objective: The aim of this study was to examine the role and molecular mechanism of the long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) in lipid metabolic reprogramming in hepatocellular carcinoma (HCC).

Methods: The effects of SNHG6 knockdown on the proliferative and metastatic capacities of Huh7 and LM3 cells were assessed using CCK-8 assays, colony formation assays, and Transwell migration and invasion assays. Lipid alterations were assessed using LipidTOX staining, triglyceride (TG) quantification, and non-targeted metabolomics. Downstream genes and signaling pathways were analyzed by RNA sequencing, quantitative reverse transcription polymerase chain reaction, and Western blotting. Rescue experiments were conducted by overexpressing stearoyl-coenzyme A desaturase (SCD) in SNHG6-knockdown cells. The regulation of SCD expression by SNHG6 via the AMPK/ sterol regulatory element-binding protein-1 (SREBP1) axis was examined by Western blotting. Additional rescue experiments were conducted using AMPK inhibitors and overexpression of SREBP1 in SNHG6-knockdown cells.

Results: SNHG6 expression was significantly upregulated in tumor tissues from patients with HCC and was associated with poor prognosis. SNHG6 silencing reduced lipid droplet accumulation and TG content in HCC cells and suppressed cellular proliferation, migration, and invasion. Further analyses demonstrated that SNHG6 knockdown decreased SCD expression, whereas overexpression of SCD restored lipogenesis and reversed the suppression of proliferation and metastatic capacity induced by SNHG6 silencing. Mechanistically, the data suggested that SNHG6 upregulated SREBP1 expression through the AMPK signaling pathway, thereby enhancing SCD expression and promoting lipid metabolism. The reduction in lipogenesis and inhibition of proliferation and metastatic capacity induced by SNHG6 silencing were reversed by AMPK pathway inhibition and SREBP1 overexpression.

Conclusion: Taken together, these findings suggested that SNHG6 may regulate lipid metabolism in HCC by linking to SCD-centered lipogenic regulation via the AMPK/SREBP1 pathway, pointing to a potential SNHG6/AMPK/SREBP1/SCD signaling axis.