한빛사논문
- 조회3,305
Abstract
Chi Luo1*, Ji-Hong Lim1*†, Yoonjin Lee1,2, Scott R. Granter3, Ajith Thomas1, Francisca Vazquez1,4,5, Hans R. Widlund6 & Pere Puigserver1
1Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. 2Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. 3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 4Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. 5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. 6Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. †Present address: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju, Chungcheongbuk-do 380-701, South Korea.
* These authors contributed equally to this work.
Correspondence to : Pere Puigserver
Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis1, 2. 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 stress3 and reprograms melanoma metabolism to influence drug sensitivity and survival4, 5. 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 metastasis6, 7, 8. Inhibition of BRAFV600E using vemurafenib9, 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.
논문정보
- Research article
- 2016년 09월 (BRIC 등록일 2016-09-21)
- 국외 연구진
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