C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors

Barroilhet, Lisa; Yang, Junzheng; Hasselblatt, Kathleen T; Paranal, RM; Ng, Shu‐Kay; Rauh‐Hain, J. Alejandro; Welch, W.; Bradner, JE; Rs, Berkowitz; Ng, S-W

doi:10.1038/onc.2012.380

Cited by 37 publications

(43 citation statements)

References 28 publications

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“…Standard immunohistochemistry (IHC) with microwave in 0.1 M citrate buffer (pH 6.0) as the antigen retrieval method was performed on FFPE sections using reagents from Vector Laboratories, Inc (Burlingame, CA, USA) as described before [14]. Antibodies used in this study are listed in Supplementary Table S1.…”

Section: Methodsmentioning

confidence: 99%

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

Worley

Liu

Hua

et al. 2015

European Journal of Cancer

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BACKGROUND Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood. METHODS We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin-embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments. RESULTS PTEN was significantly lost in both endometriosis and invasive tumor tissues, while estrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2, and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p≤0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodeling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker WT1 in OCCC, while endometriotic tissues showed significant co-expression of WT1 and ER. CONCLUSIONS Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic program for lineage-specific transformation of endometriosis to OCCC.

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Section: Methodsmentioning

confidence: 99%

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

Worley

Liu

Hua

et al. 2015

European Journal of Cancer

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“…1–5 CtBP1 was first identified through its interaction with the C-terminal region of the adenovirus E1A oncoprotein and ability to modulate E1A transforming activities. 6, 7 CtBP functions as a transcriptional regulator by tethering chromatin remodeling proteins, such as histone deacetylases, methyl transferases, and demethylases, to DNA bound transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design of a High Affinity Inhibitor to Human CtBP

et al. 2015

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Oncogenic transcriptional coregulators C-terminal Binding Protein (CtBP) 1 and 2 possess regulatory D-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains that provide an attractive target for small molecule intervention. Findings that the CtBP substrate 4-methylthio 2-oxobutyric acid (MTOB) can interfere with CtBP oncogenic activity in cell culture and in mice confirm that such inhibitors could have therapeutic benefit. Recent crystal structures of CtBP 1 and 2 revealed that MTOB binds in an active site containing a dominant tryptophan and a hydrophilic cavity, neither of which are present in other D2-HDH family members. Here we demonstrate the effectiveness of exploiting these active site features for design of high affinity inhibitors. Crystal structures of two such compounds, phenylpyruvate (PPy) and 2-hydroxyimino-3-phenylpropanoic acid (HIPP), show binding with favorable ring stacking against the CtBP active site tryptophan and alternate modes of stabilizing the carboxylic acid moiety. Moreover, ITC experiments show that HIPP binds to CtBP with an affinity greater than 1000-fold over that of MTOB and enzymatic assays confirm that HIPP substantially inhibits CtBP catalysis. These results, thus, provide an important step, and additional insights, for the development of highly selective antineoplastic CtBP inhibitors.

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“…Taken together, these results demonstrate that the CtBP2 protein level was regulated by a CHIP-dependent ubiquitin-proteasome pathway. UV irradiation decreases the protein level of CtBPs in cancer cells, and CtBPs are stabilized by MG132 treatment [15]. Our data showed that CHIP depletion resulted in up-regulation of the steady-state level of CtBP2 (Fig.…”

Section: Ctbp2 Is Regulated By Chip In a Ubiquitin-proteasome-dependementioning

confidence: 57%

“…In addition, high expression of both proteins has been reported in colon cancer [14]. Recently, elevated CtBP2 has been shown to play a role in ovarian tumorization by modulating histone deacetylase activity [15]. Collectively, these studies indicate that abundance of CtBP proteins is a crucial factor in tumorization and understanding how CtBP proteins are regulated is important.…”

Section: Introductionmentioning

confidence: 97%