Abstract
de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation of many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in cancers. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis, especially in melanomas. Elevated DNFA gene expression depends on the SREBP1 transcription factor in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, regulating their expression by recruiting RNA polymerase II to promoters for productive transcription elongation. We find that SREBP1-regulated DNFA represents a survival trait in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after the BRAF/MEK signaling pathway is blocked (e.g. by BRAF inhibitors), and DNFA expression remains higher in melanoma cells resistant to vemurafenib treatment than in untreated cells. Accordingly, DNFA pathway inhibition, whether by direct targeting of SREBP1 with antisense oligonucleotides, or through combinatorial effects of multiple DNFA enzyme inhibitors, exerts potent cytotoxic effects on both BRAFi-sensitive and -resistant melanoma cells. Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.
Highlights
Cancer cells characteristically achieve hallmark traits that facilitate proliferation, survival, and metastasis[1,2,3]
We analyzed the expression of five major de novo fatty acid synthesis (DNFA) enzymes stearoyl-CoA desaturase (SCD), fatty acid synthase (FASN) (Fig. 1a,b), ATP citrate lyase (ACLY), ACSS2 (Supplementary Fig. 1a,b) and acetyl-CoA carboxylase (ACACA) (Supplementary Fig. 2a) using RNA-Seq www.nature.com/scientificreports data from 30 diverse cancer types in The Cancer Genome Atlas (TCGA)
Four DNFA enzymes – SCD, FASN, ACLY and ACSS2 – exhibit the highest levels of mRNA expression in skin cutaneous melanoma (SKCM) compared to other tumor types, whereas expression of ACACA is less elevated in melanomas (Supplementary Fig. 2a)
Summary
Cancer cells characteristically achieve hallmark traits that facilitate proliferation, survival, and metastasis[1,2,3]. Supposed tumor cell dependence on a single oncogenic driver or pathway to sustain proliferation and/ or survival has guided the development of targeted cancer therapies[34,35]. Resistance to targeted therapies related to reactivation or bypass of downstream signaling pathways is common[41] It is unclear whether oncogene alterations maintain hallmark traits such as DNFA in malignant tumors. We demonstrate the molecular mechanism by which SREBP1 controls DNFA gene transcription in melanoma cells, revealing a regulatory role for RNA polymerase II pause/release. Our cellular analyses further reveal crucial roles for elevated DNFA gene expression in cell proliferation and survival, regardless of whether they are sensitive or resistant to targeted therapies (e.g., BRAF inhibitors)
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