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

Publication date: Jan 13, 2020

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 ? coactivator 1-? (PGC1?) expression that maintains cell survival cues by promoting mitochondrial function, but also suppresses metastatic spread. Here, we show that PGC1? expression in melanoma cells was silenced by chromatin modifications that involve promoter H3K27 trimethylation. Pharmacological EZH2 inhibition diminished H3K27me3 histone markers, increased PGC1? expression, and functionally suppressed invasion within PGC1?-silenced melanoma cells. Mechanistically, PGC1? 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 PGC1? and an association with the inherent metabolic state of the tumor.

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Concepts Keywords
Chromatin Cancer
Coactivator Medicine
Epigenetic Epigenetics
EZH2 Melanoma
Histone Branches of biology
Lesion Subset melanomas
Malignant Melanoma Initial primary melanoma
Melanoma Control melanoma metastasis
Melanomas Disease
Metastasis PGC1 expression melanoma
Metastasize RTT
Metastatic EZH2
Mitochondrial WNT5A
Oncogene H3K27me3
Peroxisome Metastasis
Receptor
Transcription
Transcription Factor
Tumor
Vivo

Semantics

Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
pathway KEGG Peroxisome
disease MESH metastasis
disease MESH tumor

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