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SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth.

ABSTRACT: Chronic inflammation is strongly associated with prostate cancer pathogenesis. Transducin ?-like protein (TBL1) and Transducin ?-like 1X-linked receptor 1 (TBLR1) have been identified recently as a coactivator for NF-?B-mediated transcription; however, the underlying mechanism by which TBL1 and TBLR1 activate NF-?B function during inflammation remains unknown. Here, we demonstrate that cytokine production is significantly elevated in androgen-independent PC-3 prostate cancer cells compared with androgen-dependent LNCaP prostate cancer cells. Elevated cytokine production positively correlates with the TBL1 and TBLR1 SUMOylation level in PC-3 cells. We show that both TBL1 and TBLR1 are SUMOylated in response to TNF-? treatment, and this increases formation of the TBL1-TBLR1-NF-?B complex, which leads to NF-?B-mediated transcriptional activation of cytokine gene expression. Conversely, SENP1-mediated deSUMOylation of TBL1 and TBLR1 inhibits NF-?B-target gene expression by dissociating TBL1 and TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex. TBL1 knockdown substantially suppresses inflammatory signaling and PC-3 cell proliferation. Collectively, these results suggest that targeted SUMOylation of TBL1 and TBLR1 may be a useful strategy for therapeutic treatment of androgen-independent prostate cancer.

SUBMITTER: Park SY

PROVIDER: S-EPMC5173046 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth.

Park Soo-Yeon SY Na Younghwa Y Lee Mee-Hee MH Seo Jae-Sung JS Lee Yoo-Hyun YH Choi Kyung-Chul KC Choi Hyo-Kyoung HK Yoon Ho-Geun HG

Oncotarget 20160701 27

Chronic inflammation is strongly associated with prostate cancer pathogenesis. Transducin β-like protein (TBL1) and Transducin β-like 1X-linked receptor 1 (TBLR1) have been identified recently as a coactivator for NF-κB-mediated transcription; however, the underlying mechanism by which TBL1 and TBLR1 activate NF-κB function during inflammation remains unknown. Here, we demonstrate that cytokine production is significantly elevated in androgen-independent PC-3 prostate cancer cells compared with ...[more]

PMID: 27129164

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Project description:The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development.Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3.We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n?=?498) and a prostate cancer tissue microarray (n?=?256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more accurate prognosis in primary prostate cancer.In contrast to the majority of previous reports suggesting tumor suppressive functions in other cancers, our observations identify a clear oncogenic role for ING3, which acts as a co-activator of AR in prostate cancer. Data from TCGA and our previous and current tissue microarrays suggest that ING3 levels correlate with AR levels and that in patients with low levels of the receptor, ING3 level could serve as a useful prognostic biomarker.

Dataset Information

SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth.

Publications

SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth.

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