title: A PGC1α-mediated transcriptional axis suppresses melanoma metastasis.
abstract: Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis. Although metabolic reprogramming is tightly associated with tumour progression, the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1α is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms melanoma metabolism to influence drug sensitivity and survival. Here, we provide data indicating that PGC1α suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1α expression inversely correlates with vertical growth in human melanoma specimens. PGC1α silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1α reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1α levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1α directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis. Inhibition of BRAFV600Eusing vemurafenib, independently of its cytostatic effects, suppresses metastasis by acting on the PGC1α-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1α maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Chi
authors: C
authors: Luo
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Ji-Hong
authors: JH
authors: Lim
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Yoonjin
authors: Y
authors: Lee
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Scott R
authors: SR
authors: Granter
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Ajith
authors: A
authors: Thomas
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Francisca
authors: F
authors: Vazquez
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Hans R
authors: HR
authors: Widlund
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Pere
authors: P
authors: Puigserver
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control*; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000077484:Vemurafenib
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497450:ID2 protein, human; D007211:Indoles; D051797:Inhibitor of Differentiation Protein 2; D016023:Integrins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013449:Sulfonamides; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D000077484:Vemurafenib