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 6

TCF12/WNT5A regulates melanoma migration.

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TCF12/WNT5A regulates melanoma migration. (A) In highly invasive A375 me...
(A) In highly invasive A375 melanoma cells, depletion of WNT5A by shRNA compromises its migratory ability (n = 3). (B and C) In nonmetastatic A375P melanoma cells, increased metastasis by loss of PGC1α can be prevented by depletion of WNT5A (B) or by blocking WNT5A interaction with its receptor (C) (n = 3). (D and E) Knocking down TCF12 by siRNA compromises migration in both A375 (D) and A375P-shPGC1α cells (E). (F) In contrast, TCF12 overexpression increases A375P cell migration (n = 3). (G) Expression levels of WNT5A predict survival of patients with early stage melanoma. (H) TCF12 expression correlates with survival of patients with metastatic melanoma. (I) Diagram depicting the regulation of melanoma metastasis by PGC1α. EZH2-dependent H3K27me3 suppresses PGC1α expression in melanoma. PGC1α, upon downregulation, can trigger ID2/TCF4-dependent activation of the integrin/FAK pathway, as previously reported, and at the same time instigate TCF12-mediated WNT5A expression to stabilize YAP. Both integrin/FAK and YAP work coordinately to drive melanoma metastasis. Quantitative results were analyzed by Student’s t test or 1-way ANOVA (B, C, E), while survival analysis was done by log-rank (Mantel-Cox) test. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001.