H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP
Chi Luo, … , Hans R. Widlund, Pere Puigserver
Chi Luo, … , Hans R. Widlund, Pere Puigserver
Published January 13, 2020
Citation Information: J Clin Invest. 2020;130(2):853-862. https://doi.org/10.1172/JCI130038.
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Research Article Cell biology Oncology

H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP

Abstract

Oncogene-targeted and immune checkpoint therapies have revolutionized the clinical management of malignant melanoma and now offer hope to patients with advanced disease. Intimately connected to patients’ overall clinical risk is whether the initial primary melanoma lesion will metastasize and cause advanced disease, but underlying mechanisms are not entirely understood. A subset of melanomas display heightened peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1α) expression that maintains cell survival cues by promoting mitochondrial function, but also suppresses metastatic spread. Here, we show that PGC1α expression in melanoma cells was silenced by chromatin modifications that involve promoter H3K27 trimethylation. Pharmacological EZH2 inhibition diminished H3K27me3 histone markers, increased PGC1α expression, and functionally suppressed invasion within PGC1α-silenced melanoma cells. Mechanistically, PGC1α silencing activated transcription factor 12 (TCF12), to increase expression of WNT5A, which in turn stabilized YAP protein levels to promote melanoma migration and metastasis. Accordingly, inhibition of components of this transcription-signaling axis, including TCF12, WNT5A, or YAP, blocked melanoma migration in vitro and metastasis in vivo. These results indicate that epigenetic control of melanoma metastasis involved altered expression of PGC1α and an association with the inherent metabolic state of the tumor.

Authors

Chi Luo, Eduardo Balsa, Elizabeth A. Perry, Jiaxin Liang, Clint D. Tavares, Francisca Vazquez, Hans R. Widlund, Pere Puigserver

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Figure 2

Expression of PGC1α inversely correlates with Hippo-YAP activity in melanoma.

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Expression of PGC1α inversely correlates with Hippo-YAP activity in mela...
(A) Treatment with 5 μM PLX4032 overnight increases PGC1α expression, but suppresses YAP protein abundance in A375P melanoma cells (n = 3). (B) Comparison of YAP protein, mRNA transcript, and transcriptional activity between PGC1α-positive A375P and PGC1α-negative A375 melanoma cells (n = 3). (C) YAP protein abundance is higher in a panel of human melanoma cell lines with low PGC1α expression. (D) Inverse correlation between PGC1α expression and various YAP target genes in different human melanoma cell lines according to CCLE data set. (E) In TCGA skin melanoma data set, samples with higher PGC1α mRNA transcript display lower levels of YAP protein measured by RPPA. Analysis was done by Mann-Whitney U test. (F) In TCGA skin melanoma data set, higher PGC1α mRNA expression correlates with lower YAP activity reflected by the expression level of its target genes. Of note, YAP1 mRNA transcript is comparable between the 2 groups. (G) Inhibition of EZH2 by GSK126 that increases PGC1α expression also suppresses YAP activity in A375 melanoma cells (n = 3). Quantitative results, if not otherwise indicated, were analyzed by Student’s t test. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001.