Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin, Lingyan; Garcia, Jesse; Chan, Emily; Cruz, Cecile de la; Segal, Ehud; Merchant, Mark; Kharbanda, Samir; Raisner, Ryan; Haverty, Peter M.; Modrušan, Zora; Ly, Justin Q.; Choo, Edna F.; Kaufman, Susan; Beresini, Maureen H.; Romero, F. Anthony; Magnuson, Steven; Gascoigne, Karen E.

doi:10.1158/0008-5472.can-17-0314

Cited by 129 publications

(117 citation statements)

References 40 publications

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“…The results showed that CBP30 abolished FSK-induced PAPP-A expression in PKD cells ( Figure 2I). To determine whether the CBP inhibition can also abolish PAPP-A expression in vivo, we treated PKD1 RC/RC mice with the 30 mg/kg CBP inhibitor GNE-049 twice a day for 3 days orally (76). We found a significant reduction in PAPP-A expression in mice treated with CBP inhibitor compared with the vehicle-treated mice ( Figure 2J).…”

Section: Papp-a Levels Increase With the Progression Of Cystic Diseasementioning

confidence: 95%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

JCI Insight

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Section: Papp-a Levels Increase With the Progression Of Cystic Diseasementioning

confidence: 95%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

JCI Insight

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“…Interestingly, we showed that a number of the AR coregulators were AR regulated and that enhanced expression of a subset of these coregulators was observed in castration-challenged PC cells ectopically overexpressing AR (Urbanucci et al 2008). Among the androgen-regulated coregulators identified were amplified in breast cancer 1 (AIB1) and CBP, both HATs which have been shown to increase nuclear receptors' activities and are implicated in mechanisms of drug resistance (Chang & Wu 2012, Culig 2016, Jin et al 2017.…”

Section: The Androgen Receptor Drives Chromatin Relaxation As An Oncomentioning

confidence: 99%

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Braadland

Urbanucci

2019

Endocrine-Related Cancer

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Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatinassociated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

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“…While investigating the possible mechanisms that may be involved in the transcriptional regulation of ABCG4, through bioinformatic tools, we found a putative CREB binding site (‐710ACGCGGGTGCCGCAGC‐695) close to the transcription initiation site of ABCG4 gene. Recently, it was shown that overexpression of CREB promotes cancer progression and metastasis and is associated with chemoresistance and androgen‐independence in PCa . With this background, we then checked whether CREB plays a role in Dox‐induced ABCG4 regulation in DU‐145 cells.…”

Section: Resultsmentioning

confidence: 99%

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

Mallappa

Neeli

Karnewar

et al. 2019

Molecular Carcinogenesis

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Multidrug resistance mediated by ATP‐binding cassette (ABC) transporters remains a major impediment to cancer chemotherapy. In the present study, we documented that doxorubicin (Dox) or cisplatin‐induced prostate cancer (PCa) chemoresistance is predominantly mediated by the induction of ABCG4 in androgen‐independent PCa cells. Treatment of DU‐145 or PC‐3 cells with Dox significantly enhanced the expression of ABCG4 that resulted in the efflux of intracellular Dox. However, incubation of cells with ABCG4 short hairpin RNA resulted in a significant accumulation of Dox and sensitized cells to Dox‐induced cytotoxicity. Interestingly, simvastatin synergistically potentiated Dox‐induced cytotoxicity by inhibiting ABCG4 in DU‐145 and DU‐145 Doxres cells. Mechanistically, ABCG4 expression was regulated redox‐dependently by intracellular glutathione (GSH) levels. Treatment of cells with N‐acetylcysteine or simvastatin restored Dox‐induced depletion of GSH levels that in turn inhibited ABCG4 levels. In addition, a reduction in GSH levels by Dox caused a nuclear factor‐κB dependent enhancement of c‐Myc expression, which led to cAMP‐regulatory element‐binding protein (CREB) activation. Furthermore, chromatin immunoprecipitation experiments revealed that Dox‐induced CREB activation transcriptionally upregulates ABCG4 expression. These results were further confirmed in an in vivo PCa xenograft mice model. Combination of simvastatin and Dox significantly regressed the tumor growth and size with no noticeable Dox‐induced cardiotoxic side effects. Intriguingly, DU‐145 cells with stably depleted ABCG4 levels not only significantly delayed the development of the tumor but also greatly sensitized the tumor to a low dose of Dox that resulted in complete tumor regression. Collectively, this data reinforces a novel function of ABCG4 in Dox‐mediated chemoresistance, and as a potential therapeutic target in drug‐induced PCa chemoresistance.

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Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Cited by 129 publications

References 40 publications

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

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