GSE204703
USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer
SREBP2 controls the expression of enzymes involved in the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol but also provides substrates for protein prenylation, and that is frequently deregulated in cancer. We show here that SREBP2 is a novel substrate for the deubiquitinating enzyme USP28 and that USP28 regulates SREBP2 stability independent of FBXW7. Inhibition of USP28 reduces MVP activity and renders cancer cells highly sensitive to MVP inhibition by statins. Moreover, statin sensitivity of USP28 depleted cells was rescued by the addition of geranyl-geranyl-pyrophosphate, a substrate for protein prenylation. We also provide evidence that SREBP2 participates in the regulation of gene expression signature associated with squamous cell carcinoma (SCC) and that SREBP2 and enzymes of the MVP are overexpressed in SCC from different tissue origins. Finally, deletion of SREBP2 attenuated tumour growth in a mouse model of lung cancer. Our findings suggest that SREBP2 is a novel substrate for USP28 and that combinatorial targeting of the MVP together with USP28 inhibition could be a therapeutic strategy for the treatment of squamous cell carcinomas. Overall design: Comparative gene expression profiling analysis of RNA-seq data for A431 cells and its KD derivatives (shUSP28_1, shUSP28_2, shSREBP2_1, shSREBP2_2, and shREN [control]).