Epigenetic silencing of DACH1 induces loss of transforming growth factor-<i>β</i>1 antiproliferative response in human hepatocellular carcinoma

Zhu, Huajian; Wu, Kongming; Wu, Yan; Hu, Ling; Yuan, Jing; Dong, Yan; Li, Yazhuo; Kunyu, Jing; Yang, Yunsheng; Guo, Mingzhou

doi:10.1002/hep.26587

Cited by 57 publications

(57 citation statements)

References 31 publications

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“…Genomic DNA from ccRCC tissues and cell lines was modified by sodium bisulfite treatment as previously described (17). CpG island spanning the KLF6 gene was found ( Supplementary Fig.…”

Section: Methylation-specific Pcrmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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“…Genomic DNA from ccRCC tissues and cell lines was modified by sodium bisulfite treatment as previously described (17). CpG island spanning the KLF6 gene was found ( Supplementary Fig.…”

Section: Methylation-specific Pcrmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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“…DNA methylation may serve as diagnostic, prognostic, chemo-sensitive and radio-sensitive markers [30]–[35]. Silenced expression of the key component by DNA methylation in cancer related signaling pathway may become the therapeutic target [34]–[37].…”

Section: Discussionmentioning

confidence: 99%

Methylation of DACT2 Promotes Papillary Thyroid Cancer Metastasis by Activating Wnt Signaling

et al. 2014

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Thyroid cancer is the most common endocrine malignant disease and the incidence is increasing. DACT2 was found frequently methylated in human lung cancer and hepatocellular carcinoma. To explore the epigenetic change and the role of DACT2 in thyroid cancer, 7 thyroid cancer cell lines, 10 cases of non-cancerous thyroid tissue samples and 99 cases of primary thyroid cancer samples were involved in this study. DACT2 was expressed and unmethylated in K1, SW579, FTC-133, TT, W3 and 8505C cell lines. Loss of expression and complete methylation was found in TPC-1 cells. Restoration of DACT2 expression was induced by 5-aza-2′deoxycytidine treatment. It demonstrates that the expression of DACT2 was regulated by promoter region methylation. In human primary papillary thyroid cancer, 64.6% (64/99) was methylated and methylation of DACT2 was related to lymph node metastasis (p<0.01). Re-expression of DACT2 suppresses cell proliferation, invasion and migration in TPC-1 cells. The activity of TCF/LEF was inhibited by DACT2 in wild-type or mutant β-catenin cells. The activity of TCF/LEF was increased by co-transfecting DACT2 and Dvl2 in wild-type or mutant β-catenin cells. Overexpression of wild-type β-catenin promotes cell migration and invasion in DACT2 stably expressed cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were decreased and the level of phosphorylated β-catenin (p-β-catenin) was increased after restoration of DACT2 expression in TPC-1 cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were increased and the level of p-β-catenin was reduced after knockdown of DACT2 in W3 and SW579 cells. These results suggest that DACT2 suppresses human papillary thyroid cancer growth and metastasis by inhibiting Wnt signaling. In conclusion, DACT2 is frequently methylated in papillary thyroid cancer. DACT2 expression was regulated by promoter region methylation. DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling.

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“…A number of genes involved in tumorigenesis have been shown to act as either oncogenes or tumor suppressor genes, depending on the cellular context (41). For instance, transforming growth factor beta-1 has been known to act, in a context-dependent manner (42), as an oncogene (43,44) or a tumor suppressor (45). It is likely that, H2ac may also play dual roles in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3′-UTR interactions in breast cancer cells

Su¹,

Tzeng²,

Cheng³

et al. 2013

Nucleic Acids Research

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A replication-dependent histone H2A isotype, H2ac, is upregulated in MCF-7 cells and in estrogen receptor-positive clinical breast cancer tissues. Cellular depletion of this H2A isotype leads to defective estrogen signaling, loss of cell proliferation and cell cycle arrest at G0/G1 phase. H2ac mediates regulation of estrogen receptor target genes, particularly BCL2 and c-MYC, by recruiting estrogen receptor alpha through its HAR domain and facilitating the formation of a chromatin loop between the promoter, enhancer and 3′-untranslated region of the respective genes. These findings reveal a new role for histone isotypes in the regulation of gene expression in cancer cells, and suggest that these molecules may be targeted for anti-cancer drug discovery.

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Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma

Cited by 57 publications

References 31 publications

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Methylation of DACT2 Promotes Papillary Thyroid Cancer Metastasis by Activating Wnt Signaling

An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3′-UTR interactions in breast cancer cells

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