Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate Cancer

Halkidou, Kalipso; Gaughan, Luke; Cook, Susan; Leung, Hing Y.; Neal, David E.; Robson, Craig

doi:10.1002/pros.20022

Cited by 459 publications

(299 citation statements)

References 46 publications

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“…(Kim et al, 2001;Mehnert and Kelly, 2007;Yoshikawa et al, 2007). In prostate cancer, HDAC-1 overexpression has been noted in three different studies (Patra et al, 2001;Halkidou et al, 2004;Weichert et al, 2008a). The question of how HDACs become overexpressed is still not entirely clear, but one possible mechanism is through regulation by miRNAs.…”

Section: Discussionmentioning

confidence: 99%

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

et al. 2009

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Section: Discussionmentioning

confidence: 99%

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

et al. 2009

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“…The clinical implication of the preferential activity of R306465 towards HDAC1 compared to HDAC6, however, is difficult to predict. Histone deacetylase 1 is key for tumour cell proliferation, and found to be upregulated in hormone refractory prostate cancer and breast cancer (Kawai et al, 2003;Halkidou et al, 2004). Although HDAC6 activity does not drive tumour cell proliferation, HDAC6 has been shown to regulate the response to misfolded protein stress and its inhibition has synergistic effects with Bortezomib, which is administered in relapsed multiple myeloma (Kawaguchi et al, 2003;Bali et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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“…For example, increased global levels of Histone H3 lysine 4 dimethylation and H3K18 acetylation are statistically linked to an increased risk of tumor recurrence (Bianco-Miotto et al, 2010). In line with this, epigenetic enzymes interpreting and modifying histones are often aberrantly expressed in PrCa (Cooper and Foster, 2009), such as class I HDACs, which are overexpressed in aggressive and hormone-refractory PrCa, thus contributing to androgen-independent, lethal PrCa's (Halkidou et al, 2004;Weichert et al, 2008). Eight KDMs are highly expressed in PrCa's (Metzger et al, 2005;Kahl et al, 2006;Wissmann et al, 2007).…”

Section: Introductionmentioning

confidence: 92%

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

et al. 2011

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Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genomewide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD-and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHDfinger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.

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Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate Cancer

Abstract: This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence.

Cited by 459 publications

References 46 publications

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

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