H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP
Chi Luo, Eduardo Balsa, Elizabeth A. Perry, Jiaxin Liang, Clint D. Tavares, Francisca Vazquez, Hans R. Widlund, Pere Puigserver
Chi Luo, Eduardo Balsa, Elizabeth A. Perry, Jiaxin Liang, Clint D. Tavares, Francisca Vazquez, Hans R. Widlund, Pere Puigserver
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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 4

YAP is required for melanoma migration and metastasis instigated by loss of PGC1α.

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YAP is required for melanoma migration and metastasis instigated by loss...
(A) In highly invasive, PGC1α-negative A375 melanoma cells, depletion of YAP by shRNA compromises its migratory ability (n = 3). (B) In the highly migratory murine melanoma cell line B16BL6, depletion of YAP by shRNA suppresses its invasiveness in congenic mice (n = 3 for qPCR and n = 5 mice per group). (C and D) In PGC1α-positive A375P and G361 melanoma cells, the increased metastasis by loss of PGC1α can be prevented by depletion of YAP, as measured by in vivo lung colonization assay (n = 6–16 mice per group). Quantitative results were analyzed by Student’s t test (A and B) or 1-way ANOVA (D). Data are shown as mean ± SEM if not otherwise indicated. *P < 0.05; **P < 0.01; ***P < 0.005.