Dataset Information

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells.

ABSTRACT: The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second-generation inhibitors of AR signaling. Because current AR inhibitors target a functioning C-terminal ligand-binding domain (LBD), the identification and characterization of cofactors interacting with the N-terminal domain (NTD) of AR may lead to new approaches to target AR signaling in CRPC. Using a pull-down approach coupled with proteomics, we have identified Hsp70 as a cofactor for the NTD of AR in prostate cancer cells. Hsp70 inhibition using siRNA or small molecules indicated that Hsp70 played an important role in the expression and transactivation of endogenous AR. Prostate-specific antigen (PSA) promoter/enhancer-driven luciferase assays showed that Hsp70 was also required for transactivation of AR mutant lacking LBD. Furthermore, clonogenic assays showed that an Hsp70 inhibitor, either alone or in synergy with enzalutamide, can inhibit the proliferation of 22Rv1, a widely used enzalutamide-resistant CRPC prostate cancer cell line. These findings suggest that Hsp70 is a potential therapeutic target for the treatment of enzalutamide-resistant CRPC.

SUBMITTER: Dong J

PROVIDER: S-EPMC6318070 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells.

Dong Jun J Wu Zeyu Z Wang Dan D Pascal Laura E LE Nelson Joel B JB Wipf Peter P Wang Zhou Z

Molecular cancer therapeutics 20181008 1

The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second-generation inhibitors of AR signaling. Because current AR inhibitors target a functioning C-terminal ligand-binding domain (LBD), the identification and characterization of cofactors interacting with the N-terminal domain (NTD) of AR may lead to new approaches to target AR signaling in ...[more]

PMID: 30297360

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Project description:Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.

Dataset Information

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells.

Publications

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells.

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