Elevated de novo fatty acid biosynthesis gene expression promotes melanoma cell survival and drug resistance

Elevated de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation in many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in melanomas. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis. Elevated DNFA gene expression depends on transcription factor SREBP1 in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, directly regulating transcription via RNA polymerase II recruitment and productive elongation. We find that SREBP1-regulated DNFA represents an intrinsic survival mechanism in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after pro-survival signaling pathways are blocked (e.g. by the BRAF inhibitor vemurafenib). Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.