Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.
Mol Cell, 2020/01/02;77(1):120-137.e9.
Vivas-García Y[1], Falletta P[1], Liebing J[2], Louphrasitthiphol P[1], Feng Y[3], Chauhan J[1], Scott DA[3], Glodde N[2], Chocarro-Calvo A[4], Bonham S[5], Osterman AL[3], Fischer R[5], Ronai Z[3], García-Jiménez C[6], Hölzel M[2], Goding CR[7]
Affiliations
PMID: 31733993DOI: 10.1016/j.molcel.2019.10.014
Impact factor: 19.328
Abstract
Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.
Keywords: ATF4; MITF; fatty acid saturation; melanoma; metastatic dissemination; phenotype switching; stearoyl CoA desaturase
MeSH terms
Adaptation, Physiological; Animals; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Fatty Acids; Humans; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Neoplasm Invasiveness; Phenotype; Signal Transduction; Stearoyl-CoA Desaturase
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