SNHG1, interacting with SND1, contributes to sorafenib resistance of liver cancer cells by increasing m6A‐mediated SLC7A11 expression and promoting aerobic glycolysis

Abstract

AbstractAerobic glycolysis plays an important role in multidrug resistance of cancer cells. Here, we screened different expressed lncRNAs associated with sorafenib resistance of liver cancer cells, by intersecting the bioinformatics analyses of TCGA and GEO (the GSE62813 dataset) databases. Our results revealed that the 18 upregulated lncRNAs in the intersection are associated with and enriched in metabolism of small molecule organic acids, suggesting their potential in glycolysis. The lncRNA small nucleolar RNA host gene 1 (Snhg1) was chosen as a potential regulator of aerobic glycolysis in liver cancer cells, for its significant promotion on lactate production. Gain‐ and loss‐of‐function experiments mediated by Crispr‐Cas9 technique in HepG2 cells indicated that Snhg1 promoted cell proliferation, invasion, sorafenib resistance, and aerobic glycolysis. In the mechanism exploration, we found that Snhg1 can interact with SND1 protein, a famous RNA binding protein and recently identified “Reader” of N6‐methyladenosine (m6A). SND1 was demonstrated to be positively regulated by Snhg1 and had similar promoting effects on proliferation, invasion, sorafenib resistance, and aerobic glycolysis of HepG2 cells. SND1 bound with and promoted the expression of SLC7A11, an aerobic glycolysis regulator. Furthermore, either silencing SLC7A11 or blocking aerobic glycolysis with 2‐deoxy‐d‐glucose (2‐DG) was able to reverse the promotion of Snhg1 overexpression on malignancy, sorafenib resistance, and aerobic glycolysis of HepG2 cells. Finally, in a liver cancer xenograft mouse model, we found that formed tumors with Snhg1‐knocked‐down HepG2 cells were more sensitive to sorafenib administration. Altogether, SNHG1 contributes to sorafenib resistance of liver cancer cells by promoting SND1‐m6A‐SLC7A11‐mediated aerobic glycolysis.