H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

Wu, Pei‐Chun; Lu, Jeng‐Wei; Yang, Jer-Yen; Lin, I-Hsuan; Ou, Da‐Liang; Lin, Yu‐Hsiang; Chou, Kuan-Hsien; Huang, Wenfeng; Wang, Wan-Ping; Huang, Yih‐Leh; Hsu, Chiun; Lin, Liang-In; Lin, Yueh‐Min; Shen, Chieh-Yu; Tzeng, Tsai-Yu

doi:10.1158/0008-5472.can-13-3572

Cited by 57 publications

(61 citation statements)

References 44 publications

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“…In a melanoma zebrafish model, overexpression of SETDB1 increased local invasiveness of the tumor . However, in another study, inactivation of SETDB1 promoted metastasis of lung cancer cells in zebrafish and mouse models . Interestingly, both prometastatic and antimetastatic functions of SETDB1 have been observed in lung cancer with different cell line models used .…”

Section: Discussionmentioning

confidence: 98%

Up‐regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis

et al. 2015

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Epigenetic deregulation plays an important role in liver carcinogenesis. Using transcriptome sequencing, we examined the expression of 591 epigenetic regulators in hepatitis B-associated human hepatocellular carcinoma (HCC). We found that aberrant expression of epigenetic regulators was a common event in HCC. We further identified SETDB1 (SET domain, bifurcated 1), an H3K9-specific histone methyltransferase, as the most significantly up-regulated epigenetic regulator in human HCCs. Up-regulation of SETDB1 was significantly associated with HCC disease progression, cancer aggressiveness, and poorer prognosis of HCC patients. Functionally, we showed that knockdown of SETDB1 reduced HCC cell proliferation in vitro and suppressed orthotopic tumorigenicity in vivo. Inactivation of SETDB1 also impeded HCC cell migration and abolished lung metastasis in nude mice. Interestingly, SETDB1 protein was consistently up-regulated in all metastatic foci found in different organs, suggesting that SETDB1 was essential for HCC metastatic progression. Mechanistically, we showed that the frequent up-regulation of SETDB1 in human HCC was attributed to the recurrent SETDB1 gene copy gain at chromosome 1q21. In addition, hyperactivation of specificity protein 1 transcription factor in HCC enhanced SETDB1 expression at the transcriptional level. Furthermore, we identified miR-29 as a negative regulator of SETDB1. Down-regulation of miR-29 expression in human HCC contributed to SETDB1 up-regulation by relieving its post-transcriptional regulation. Conclusion: SETDB1 is an oncogene that is frequently up-regulated in human HCCs; the multiplicity of SETDB1 activating mechanisms at the chromosomal, transcriptional, and posttranscriptional levels together facilitates SETDB1 up-regulation in human HCC. (HEPATOLOGY 2016;63:474-487)

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Section: Discussionmentioning

confidence: 98%

Up‐regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis

et al. 2015

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“…As described in the present study, JARID1D is lost and downregulated in a substantial portion of metastatic prostate tumors. The H3K9 methyltransferase SETDB1, which appears to inhibit metastasis of lung cancer cells, is strongly downregulated in lung cancer cells (53). …”

Section: Discussionmentioning

confidence: 99%

JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis

et al. 2016

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Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared to normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer.

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“…It represses a large set of genes including HOX genes for melanoma progression [127] and confers outgrowth and advantages of liver cancer cells through methylating and stabilizing the oncogenic p53 mutants [128]. Surprisingly, it has also been shown that SETDB1 cooperates with SMAD2/3 to suppress EMT and metastasis of lung cancer cells [130]. …”

Section: Permissive Histone Modifications In Emtmentioning

confidence: 99%

Epigenetic regulation of epithelial–mesenchymal transition

Sun

Fang

2016

Cell. Mol. Life Sci.

104

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Epithelial-mesenchymal transition (EMT) is an essential process for morphogenesis and organ development which reversibly enables polarized epithelial cells to lose their epithelial characteristics and acquire mesenchymal properties. It is now evident that the aberrant activation of EMT is also a critical mechanism to endow epithelial cancer cells with migratory and invasive capabilities associated with metastatic competence. This dedifferentiation program is mediated by a small cohort of pleiotropic transcription factors which in turn orchestrate a complex array of epigenetic mechanisms for the widespread changes in gene expression. Here, we review major epigenetic mechanisms with emphasis on histone modifications and discuss their implications in EMT and tumor progression. We also highlight mechanisms underlying transcription regulation concerted by various chromatin modifying proteins and EMT-inducing transcription factors at different molecular layers. Owing to the reversible nature of epigenetic modifications, a thorough understanding of their functions in EMT will not only provide new insights into our knowledge of cancer progression and metastasis, but also facilitates the development of diagnostic and therapeutic strategies for human malignancy.

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H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

Cited by 57 publications

References 44 publications

Up‐regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis

Up‐regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis

JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis

Epigenetic regulation of epithelial–mesenchymal transition

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