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Abstract
The androgen receptor (AR) is a key driver of prostate cancer development. Antiandrogens effectively inactivate the AR, but subsequent AR reactivation progresses the disease to castrate-resistant prostate cancer (CRPC). Constitutively active AR splice variants (AR-V) that function unchallenged by current AR-targeted therapies are key drivers of CRPC. Currently, very little is known about the regulation of AR-Vs at the chromatin level. Here, we show that the pioneer factor GATA2 is a critical regulator of AR-Vs. Furthermore, we demonstrate that the GATA2 cistrome in CRPC shares considerable overlap with bromodomain and extraterminal (BET) proteins and is codependent for DNA binding. GATA2 activity is compromised by BET inhibitors, which attenuates the pioneering role of GATA2 in CRPC. In all, this study indicates that GATA2 is a critical regulator of AR-V-mediated transactivation and is sensitive to BET inhibitors, signifying these agents may be efficacious in patients with CRPC which overexpress GATA2. IMPLICATIONS: We have defined novel mechanisms of AR-V and GATA2 regulation in advanced prostate cancer that could be therapeutically exploited.
Highlights
Prostate cancer is the second most commonly diagnosed cancer in men globally with 1.3 million annual diagnoses worldwide (World Health Organization, 2018)
A, CWR22Rv1 cells cultured in steroid-depleted conditions were transiently transfected with either control or GATA2 siRNAs for 24 hours prior to treatment Æ 10 mmol/L enzalutamide (Enz) for an additional 24 hours before RT-qPCR analysis of androgen receptor (AR)-target genes
Persistent AR signaling is a key driver of disease progression [3, 38], only 50% of castrate-resistant prostate cancer (CRPC) patients will respond [5, 6] to the current gold-standard AR-targeting treatments and even this is short-lived in the majority of cases
Summary
Prostate cancer is the second most commonly diagnosed cancer in men globally with 1.3 million annual diagnoses worldwide (World Health Organization, 2018). Prostate cancer growth is androgen dependent; the mainstay of treatment is androgen deprivation therapy (ADT) in combination with antiandrogens. AR signaling persists in CRPC due to several well-characterized molecular mechanisms [2], including AR gene amplification and mutation, which has justified the development of second-generation antiandrogens, such as enzalutamide and apalutamide [3, 4]. These compounds are used clinically to treat CRPC, but response rates of Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
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