Methylation of RB1 CpG island by SUV39H1/DNMT3A promotes malignant melanoma development

Abstract

Melanoma is among the most aggressive and treatment‐resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing but the significance of suppressor of variegation 3–9 homolog 1 (SUV39H1), a H3K9‐specific methyltransferase, in melanoma initiation and progression remains unclear. Here we show that SUV39H1‐mediated H3K9 trimethylation (H3K9me3) facilitates retinoblastoma (RB1) promoter CpG island methylation by interacting with DNMT3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition leading to increased peptidyl‐prolyl cis‐trans isomerase NIMA interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced RAF1/MEKs/ERKs signaling pathway activation. In a synergistic model with B16‐F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1‐overexpressing B16‐F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.Support or Funding InformationThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI18C1083).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.