SOX9-mediated UGT8 expression promotes glycolysis and maintains the malignancy of non-small cell lung cancer.

ABSTRACT

UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to small lipophilic chemicals and are associated with a wide range of diseases including cancer. The human genome contains 22 UGT genes which could be classified into four families UGT1, UGT2, UGT3, and UGT8. The UGT8 family contains only one member which utilizes UDP galactose to galactosidate ceramide. Although higher UGT8 mRNA was observed in some types of cancer, its pathological significances remain elusive. Here, by integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Genotype-Tissue Expression (GTEx) databases, we showed that UGT8 was selectively highly expressed in non-small cell lung cancer (NSCLC) and associated with worse prognosis. The transcription factor SOX9 promoted UGT8 expression in NSCLC by recognizing two putative response elements localized on the promoter region of UGT8. Silencing UGT8 impaired glycolysis and reduced the malignancy of NSCLC cells both in vitro and in vivo. On the contrary, inhibition of glycolysis by 2-deoxy-d-glucose (2-DG) significantly impaired the pro-proliferation function of UGT8 in NSCLC cells. In conclusion, our results suggest that UGT8 maintains the malignancy of NSCLC mainly via enhanced glycolysis and provides a promising therapeutic target for NSCLC.