Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer

Zhong, Sheng; Fields, C. Robert; Su, Nan; Pan, Yuan Xiang; Robertson, Keith D.

doi:10.1038/sj.onc.1210041

Cited by 121 publications

(102 citation statements)

References 47 publications

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“…This hypothesis is based on the previous reports that 5-Aza-dC reactivates the transcription of PTEN, 36 that CYLD are dominantly regulated by histone deacetylation, 44 and that the activity of p53 and FOXO3a are regulated by SIRT1-mediated histone deacetylation. 26,29 In LNCaP and PC-3 cell lines, 5-aza-dC as well as genistein, but not TSA, dramatically increased the expression of PTEN and CYLD mRNA in the absence of DNA promoter methylation.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-jB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: genistein; prostate cancer; tumor suppressor gene Genistein (4 0 ,5,7-trihydroxyflavone), a naturally occurring isoflavenoid abundant in soy products, has been identified as an inhibitor of protein tyrosine kinases, which play key roles in cell growth and apoptosis. 1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate. 6 Taken together, these findings suggest that genistein's antitumor activity may be mediated by epigenetic-based pathways. On the other hand, genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-jB) pathway, which could be mediated via AKT (AKT8 virus oncogene cellular homolog) signaling, the most important survival pathway in cellular signaling. 7 However, the precise molecular mechanism has yet to be characterized.AKT is a serine/threonine protein kinase functioning downstream of phosphatidylinositol 3-kinase (PI3K) in response to mitogen or growth factor stimulation. High-levels of AKT activation have been associated with the development and metastasis of several cancers. 8 AKT activation not only directly inhibits apoptosis by multiple mechanisms involved in inhibiting the conformational change of Bax, BAD and caspase-9 but also modulates apoptosis indirectly by influencing the activities of several transcription factors, including fork head transcription factors (FOXO) and...

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Section: Discussionmentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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“…Cylindromas are usually benign, although occasionally they can malignize (Durani et al, 2001;De Francesco et al, 2005). Additional studies have associated Cyld downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas (Strobel et al, 2002;Hashimoto et al, 2004;Hirai et al, 2004;Costello et al, 2005;Hellerbrand et al, 2007;Keats et al, 2007;Zhong et al, 2007;Massoumi et al, 2009). In the case of multiple myeloma and melanoma, it has been shown that its grade of malignancy is directly related with the silencing of CYLD, being of poor prognosis those tumors with lower expression level of CYLD (Annunziata et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD C/S ) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD C/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD C/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD C/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD C/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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“…Cystatin M is involved in regulating the activity of cathepsin B and cathepsin L, and imbalances between these proteases and cystatin M may lead to the metastatic phenotype in tumor cells (Frosch et al, 1999;Kos et al, 2000;Lah and Kos, 1998). Cystatin M expression has been reported to be diminished or lost in various forms of cancer including, (i) basal and squamous cell carcinomas of the skin (Zeeuwen, 2004), (ii) squamous cell carcinomas of the head/neck and lung (Zeeuwen et al, 2002), (iii) non-small cell lung cancer (Zhong et al, 2006), (iv) metastatic oral cancer cell lines (Vigneswaran et al, 2006), (v) malignant glioma (Kim et al, 2006), and (vi) breast cancer (Ai et al, 2006;Rivenbark et al, 2006a;Schagdarsurengin et al, 2006;Shridhar et al, 2004;Song et al, 2006;Sotiropoulou et al, 1997;Zhang et al, 2004). Cystatin M contains a large CpG island that flanks the transcription start site and spans the proximal promoter and exon 1 regions.…”

Section: Introductionmentioning

confidence: 99%

Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions

Rivenbark

Livasy

Boyd

et al. 2007

Experimental and Molecular Pathology

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CST6 is a breast tumor suppressor gene that is expressed in normal breast epithelium, but is epigenetically silenced as a consequence of promoter hypermethylation in metastatic breast cancer cell lines. In the current study, we investigated the expression and methylation status of CST6 in primary breast tumors and lymph node metastases. 25/45 (56%) primary tumors and 17/20 (85%) lymph node metastases expressed significantly lower levels of cystatin M compared to normal breast tissue. Bisulfite sequencing demonstrated CST6 promoter hypermethylation in 11/23 (48%) neoplastic lesions analyzed, including 3/11 (27%) primary tumors and 8/12 (67%) lymph node metastases. In most cases (12/23, 52%), the expression of cystatin M directly reflected CST6 promoter methylation status. In remaining lesions (8/23, 35%) loss of cystatin M was not associated with CST6 promoter hypermethylation, indicating that other mechanisms can account for loss of CST6 expression. These results show that methylation-dependent silencing of CST6 occurs in a subset of primary breast cancers, but more frequently in metastatic lesions, possibly reflecting progressionrelated genomic events. To examine this possibility, primary breast tumors and matched lymph node metastases were analyzed. In 2/3 (67%) patients, primary tumors were positive for cystatin M and negative for CST6 promoter methylation, and matched metastatic lesions lacked cystatin M expression and CST6 was hypermethylated. This observation suggests that progression-related epigenetic alterations in CST6 gene expression can accompany metastatic spread from a primary tumor site. Overall, the results of the current investigation suggest that methylation-dependent epigenetic silencing of CST6 represents an important mechanism for loss of CST6 during breast tumorigenesis and/or progression to metastasis.

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Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer

Cited by 121 publications

References 47 publications

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions

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