SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and 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), an H3K9‐specific methyltransferase, in melanom...

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Published in:The FASEB journal 2018-10, Vol.32 (10), p.5647-5660
Main Authors: Kim, Garam, Kim, Jin‐Young, Lim, Sung‐Chul, Lee, Kwang Youl, Kim, Okyun, Choi, Hong Seok
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
CpG methylation
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Methylation
DNA, Neoplasm - genetics
DNA, Neoplasm - metabolism
E2F1
Gene Expression Regulation, Neoplastic
HEK293 Cells
histone methylation
Humans
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Methylation
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
NIMA-Interacting Peptidylprolyl Isomerase - biosynthesis
NIMA-Interacting Peptidylprolyl Isomerase - genetics
prolyl isomerase
Repressor Proteins - genetics
Repressor Proteins - metabolism
Retinoblastoma Protein - biosynthesis
Retinoblastoma Protein - genetics
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Summary: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), an H3K9‐specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1‐mediated H3K9 trimethylation facilitates retinoblastoma (RB)1 promoter CpG island methylation by interacting with DNA methyltransferase 3A 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 never‐in‐mitosis A (NIMA)‐interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)‐MEK‐ERK 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.—Kim, G., Kim, J.‐Y., Lim, S.‐C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development. FASEB J. 32, 5647–5660 (2018). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201700645RRRRR