Regulation of Androgen-Responsive Transcription by the Chromatin Remodeling Factor CHD8

Menon, Tushar; Yates, Joel A.; Bochar, Daniel A.

doi:10.1210/me.2009-0421

Cited by 47 publications

(47 citation statements)

References 55 publications

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“…5A). In line with these findings, modulation of the AR-mediated transcription was recently reported for CHD8, another member of the CHD family (16). To test whether this effect was due to the impaired recruitment of AR to the promoters of AR-responsive genes, we carried out ChIP analysis and determined the AR occupancy at responsive promoters (PSA, TMPRSS2, FKBP5, ELK4, and KLK2) in control and CHD1-depleted LNCaP cells upon stimulation with DHT.…”

Section: Resultssupporting

confidence: 54%

“…CHD5 is a known tumor suppressor controlling apoptosis via the p19-p53 pathway and which is often inactivated by deletions involving the chromosomal band 1p36 (14,15). Furthermore CHD8, another member of the CHD gene family, has been suggested to play a role in androgen receptor (AR)-dependent transcription regulation in prostate cancer (16).…”

Section: Introductionmentioning

confidence: 99%

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CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

et al. 2013

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Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostate cancer. Using single-nucleotide polymorphism (SNP) arrays, we mapped a 1.3 megabase minimally deleted region including only the repulsive guidance molecule B (RGMB) and chromodomain helicase DNA-binding protein 1 (CHD1) genes. Functional analyses showed that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, prostate-specific antigen (PSA) biochemical failure (P ¼ 0.0038), and absence of ERG fusion (P < 0.0001). We found that inactivation of CHD1 in vitro prevents formation of ERG rearrangements due to impairment of androgen receptor (AR)-dependent transcription, a prerequisite for ERG translocation. CHD1 is required for efficient recruitment of AR to responsive promoters and regulates expression of known AR-responsive tumor suppressor genes, including NKX3-1, FOXO1, and PPARg. Our study establishes CHD1 as the 5q21 tumor suppressor gene in prostate cancer and shows a key role of this chromatin remodeling factor in prostate cancer biology. Cancer Res; 73(9); 2795-805. Ó2013 AACR.

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Section: Resultssupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

et al. 2013

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“…Briefly, LNCaP cells were grown in phenol red-free RPMI-1640 medium with 10% FBS (charcoal stripped) for 3 d and treated with 1 nM R1881 or vehicle for 24 h. Prepared chromatin was immunoprecipitated with anti-AR or anti-IgG antibody at 4°C overnight. The precipitated DNA was PCR amplified with primers corresponding to PSA enhancer or corresponding to the androgen-responsive elements of TMPRSS2, as previously described (25,26). The relative enrichment was shown using agarose gel electrophoresis.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

Wang

Guo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N -acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR–ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR–ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy.

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“…The COOH-terminal region of full-length CHD8 (CHD8 L ) interacts with the insulator-binding protein CTCF, with this interaction being important for insulator activity (14). CHD8 has also been implicated as a positive or negative transcriptional regulator of various genes (19,32,33,45,46). We previously showed that Chd8 Ϫ/Ϫ mice die early during embryogenesis, manifesting widespread apoptosis (28), whereas additional deletion of the tumor suppressor gene p53 ameliorated this developmental arrest (29).…”

mentioning

confidence: 99%

Histone H1 Recruitment by CHD8 Is Essential for Suppression of the Wnt–β-Catenin Signaling Pathway

Nishiyama

Skoultchi

Nakayama

2012

Molecular and Cellular Biology

123

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Members of the chromodomain helicase DNA-binding (CHD) family of proteins are thought to regulate gene expression. Among mammalian CHD proteins, CHD8 was originally isolated as a negative regulator of the Wnt-␤-catenin signaling pathway that binds directly to ␤-catenin and suppresses its transactivation activity. The mechanism by which CHD8 inhibits ␤-catenin-dependent transcription has been unclear, however. Here we show that CHD8 promotes the association of ␤-catenin and histone H1, with formation of the trimeric complex on chromatin being required for inhibition of ␤-catenin-dependent transactivation. A CHD8 mutant that lacks the histone H1 binding domain did not show such inhibitory activity, indicating that histone H1 recruitment is essential for the inhibitory effect of CHD8. Furthermore, either depletion of histone H1 or expression of a dominant negative mutant of this protein resulted in enhancement of the response to Wnt signaling. These observations reveal a new mode of regulation of the Wnt signaling pathway by CHD8, which counteracts ␤-catenin function through recruitment of histone H1 to Wnt target genes. Given that CHD8 is expressed predominantly during embryogenesis, it may thus contribute to setting a threshold for responsiveness to Wnt signaling that operates in a development-dependent manner.

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Regulation of Androgen-Responsive Transcription by the Chromatin Remodeling Factor CHD8

Cited by 47 publications

References 55 publications

CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

Histone H1 Recruitment by CHD8 Is Essential for Suppression of the Wnt–β-Catenin Signaling Pathway

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