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2016 ; 537
(7620
): 422-426
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A PGC1?-mediated transcriptional axis suppresses melanoma metastasis
#MMPMID27580028
Luo C
; Lim JH
; Lee Y
; Granter SR
; Thomas A
; Vazquez F
; Widlund HR
; Puigserver P
Nature
2016[Sep]; 537
(7620
): 422-426
PMID27580028
show ga
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. PGC1? 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 PGC1? suppresses melanoma
metastasis, acting through a pathway distinct from that of its bioenergetic
functions. Elevated PGC1? expression inversely correlates with vertical growth in
human melanoma specimens. PGC1? silencing makes poorly metastatic melanoma cells
highly invasive and, conversely, PGC1? reconstitution suppresses metastasis.
Within populations of melanoma cells, there is a marked heterogeneity in PGC1?
levels, which predicts their inherent high or low metastatic capacity.
Mechanistically, PGC1? 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 BRAF(V600E) using vemurafenib,
independently of its cytostatic effects, suppresses metastasis by acting on the
PGC1?-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1? 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.
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