Dataset Information

HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens.

ABSTRACT: We show that HEXIM1 (hexamethylene bis-acetamide inducible 1) functions as an AR (androgen receptor) co-repressor as it physically interacts with the AR and is required for the ability of anti-androgens to inhibit androgen-induced target gene expression and cell proliferation. Oncomine™ database and IHC (immunohistochemistry) analyses of human prostate tissues revealed that expression of HEXIM1 mRNA and protein are down-regulated during the development and progression of prostate cancer. Enforced down-regulation of HEXIM1 in parental hormone-dependent LNCaP cells results in resistance to the inhibitory action of anti-androgens. Conversely, ectopic expression of HEXIM1 in the CRPC (castration-resistant prostate cancer) cell line, C4-2, enhances their sensitivity to the repressive effects of the anti-androgen bicalutamide. Novel insight into the mechanistic basis for HEXIM1 inhibition of AR activity is provided by the present studies showing that HEXIM1 induces expression of the histone demethylase KDM5B (lysine-specific demethylase 5B) and inhibits histone methylation, resulting in the inhibition of FOXA1 (forkhead box A1) licensing activity. This is a new mechanism of action attributed to HEXIM1, and distinct from what has been reported so far to be involved in HEXIM1 regulation of other nuclear hormone receptors, including the oestrogen receptor.

SUBMITTER: Yeh IJ

PROVIDER: S-EPMC5705236 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens.

Yeh I-Ju IJ Song Kyung K Wittmann Bryan M BM Bai Xiaodong X Danielpour David D Montano Monica M MM

The Biochemical journal 20140901 2

We show that HEXIM1 (hexamethylene bis-acetamide inducible 1) functions as an AR (androgen receptor) co-repressor as it physically interacts with the AR and is required for the ability of anti-androgens to inhibit androgen-induced target gene expression and cell proliferation. Oncomine™ database and IHC (immunohistochemistry) analyses of human prostate tissues revealed that expression of HEXIM1 mRNA and protein are down-regulated during the development and progression of prostate cancer. Enforce ...[more]

PMID: 24844355

Similar Datasets

Project description:BACKGROUND:Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. METHODS:Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n?=?7), abiraterone (n?=?9), cabazitaxel (n?=?6), castration plus abiraterone (n?=?8), castration plus cabazitaxel (n?=?11), or vehicle and/or sham operation (n?=?23). Tumor growth was followed for about 2 months or to a volume of approximately 1000?mm3 . Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. RESULTS:Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. CONCLUSIONS:Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.

Dataset Information

HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens.

Publications

HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets