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 February 3, 2020; First 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 5

WNT5A mediates YAP regulation by PGC1α.

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WNT5A mediates YAP regulation by PGC1α. (A) Addition of WNT5A protein in...
(A) Addition of WNT5A protein in culture media increases YAP protein in a dose-dependent manner in A375P cells (n = 3). (B) Knockdown of PGC1α induces WNT5A expression in A375P cells (n = 3). (C) The expression of PGC1α and WNT5A is inversely correlated in human melanoma cell lines according to the CCLE data set. (D and E) Silencing WNT5A expression (D) or blocking WNT5A’s binding to its receptor FZD5 (E) in A375P melanoma cells is able to prevent the induction of YAP by loss of PGC1α (n = 3). (F) ID2 is able to interact with TCF12. Cell lysate from A375P melanoma cells overexpressing V5-ID2 was subject to immunoprecipitation with V5 antibody, followed by immunoblotting with TCF12 antibody. (G) Knockdown of TCF12 is able to prevent the induction of WNT5A by loss of PGC1α in A375P cells (G, n = 3). (H) Knockdown of TCF12 suppresses WNT5A expression in PGC1α-negative A375 cells (H, n = 3). (I and J) Overexpression of TCF12 boosts the activity of WNT5A promoter–driven luciferase activity (I, n = 7) and WNT5A transcription (J, n = 3) in A375P cells. Quantitative results were analyzed by Student’s t test or 1-way ANOVA (D, E, G). Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001.