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Epigenetic modification restores functional PR expression in endometrial cancer cells.

ABSTRACT: Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated tumor. Response to progestin-based therapy correlates positively with progesterone receptor (PR) expression. However, many endometrial tumors have low levels or loss of PR, limiting the clinical application of progestin. We evaluated the ability of epigenetic modulators to restore functional PR expression in Type I endometrial cancer cells with low basal PR. Treatment with the histone deacetylase inhibitor (HDACi) LBH589 induced a profound upregulation of PR mRNA. LBH589 restored PR protein expression at 24 hours and sustained expression for 72 hours, even in the presence of progesterone. LBH589 promoted a dose-dependent increase in PR protein levels, with an obvious increase with 10 nM LBH589. To investigate if the restored PR is functional as a transcription factor, we examined PR nuclear localization and expression of PRE- or Sp1-containing target genes. After treatment with LBH589 in the absence or presence of progesterone, PR nuclear expression was increased as demonstrated by Western blotting of nuclear fractions and immunostaining. Next, restored PR upregulated FoxO1, p21, and p27 and downregulated cyclin D1 in a ligand-dependent manner. Finally, LBH589 treatment induced cell cycle arrest in G1 that was further augmented by progesterone. Regulation of PR target genes was also achieved with other HDAC inhibitors, indicating that agents in this class work similarly with respect to PR. Our findings reveal that epigenetic modulators can restore endogenous functional PR expression in endometrial cancer cells and suggest that strategies to re-establish PR expression will resensitize endometrial tumors to progestin therapy.

SUBMITTER: Yang S

PROVIDER: S-EPMC3969402 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Epigenetic modification restores functional PR expression in endometrial cancer cells.

Yang Shujie S Xiao Xue X Jia Yichen Y Liu Xiaoyue X Zhang Yuping Y Wang Xinjun X Winters Christopher J CJ Devor Eric J EJ Meng Xiangbing X Thiel Kristina W KW Leslie Kimberly K KK

Current pharmaceutical design 20140101 11

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated tumor. Response to progestin-based therapy correlates positively with progesterone receptor (PR) expression. However, many endometrial tumors have low levels or loss of PR, limiting the clinical application of progestin. We evaluated the ability of epigenetic modulators to restore functional PR expression in Type I endometrial cancer cells with low basal PR. Treatment with the histone deacetylase inhibitor (HDA ...[more]

PMID: 23888956

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Project description:The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer.

Dataset Information

Epigenetic modification restores functional PR expression in endometrial cancer cells.

Publications

Epigenetic modification restores functional PR expression in endometrial cancer cells.

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