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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

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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 3

PGC1α compromises YAP stability via a proteasome-mediated pathway.

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PGC1α compromises YAP stability via a proteasome-mediated pathway.
(A an...
(A and B) Overexpression of PGC1α by adenovirus suppresses YAP protein expression and activity without affecting its mRNA transcript in A375P, A375 (A), and G361 (B) melanoma cells (n = 3). (C and D) Depletion of PGC1α by shRNA (C) or CRISPR (D) enhances YAP protein expression and activation without altering its mRNA level in multiple melanoma cell lines (n = 3). (E) YAP protein is more stable in A375P cells with PGC1α depletion. Cells were treated with 50 mg/mL of CHX for the indicated period and harvested for immunoblotting analysis (n = 3). (F) PGC1α-induced YAP degradation in A375P cells can be blocked by treatment with 10 μM of proteasome inhibitor MG132 overnight (n = 3). Quantitative results were analyzed by Student’s t test or 1-way ANOVA. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005.
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