NKX3.1 Suppresses <i>TMPRSS2–ERG</i> Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

Cai, Bin; Tian, Zheng; Gelmann, Edward P.

doi:10.1158/0008-5472.can-14-3387

Cited by 33 publications

(28 citation statements)

References 55 publications

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“…Nkx3.1 regulates the magnitude and timing of the acute response to DNA damage in prostate luminal epithelial cells. Based on our prior findings, the effect of NKX3.1 on the DNA damage response is important for cellular integrity and for prevention of pathogenic DNA lesions such as TMPRSS2-ERG rearrangement [7,16]. It is noteworthy that basal epithelial cells do not express NKX3.1 or apparently require an accelerated response to DNA repair.…”

Section: Discussionmentioning

confidence: 92%

“…Moreover, the degree of NKX3.1 protein loss in primary prostate cancer varies from levels as low as 30% of normal cell levels to 90% of normal cell levels. The degree of NKX3.1 protein loss correlates with the propensity for TMRPSS2‐ERG rearrangement, reflecting attenuated DNA repair 17. Also, lower levels of NKX3.1 correlated with higher Gleason grade and therefore diminished long‐term prognosis 16, 24.…”

Section: Discussionmentioning

confidence: 99%

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Nkx3.1 controls the DNA repair response in the mouse prostate

et al. 2015

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BACKGROUNDThe human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2‐ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.METHODSUsing both drug‐induced DNA damage and γ‐irradiation, we assayed expression of γ‐histone 2AX at time points up to 24 hr after induction of DNA damage.RESULTSWe demonstrated that expression of Nkx3.1 influenced both the timing and magnitude of the DNA damage response in the prostate.CONCLUSIONSNkx3.1 affects the DNA damage response in the murine prostate and is haploinsufficient for this phenotype. Prostate 76:402–408, 2016. © 2015 The Authors. The Prostate published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Nkx3.1 controls the DNA repair response in the mouse prostate

et al. 2015

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“…Several studies implicate androgen/AR and estrogen/ER in positive regulation of HR. In PCa, the AR-regulated prostatic tumor suppressor gene Nkx3.1 serves directly in DDR via activation of ATM and recruitment of the DNA repair machinery to sites of damage [48]. In melanoma, the tumor suppressor gene MEN1 and ERα bind to the promoters of RAD51 and BRCA1, therein activating transcription [49].…”

Section: Hormonal Regulation Of Dna Repairmentioning

confidence: 99%

Linking DNA Damage and Hormone Signaling Pathways in Cancer

Schiewer

Knudsen

2016

Trends in Endocrinology & Metabolism

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DNA damage response and repair (DDR) is a tightly controlled process that serves as a barrier to tumorigenesis. Consequently, DDR is frequently altered in human malignancy, and can be exploited for therapeutic gain either through molecularly targeted therapies, or as a consequence of therapeutic agents that induce genotoxic stress. In select tumor types, steroid hormones and cognate receptors serve as major drivers of tumor development/progression, and as such are frequently targets of therapeutic intervention. Recent evidence suggests the existence of crosstalk mechanisms linking the DDR machinery and hormone signaling pathways that cooperate to influence both cancer progression and therapeutic response. These underlying mechanisms and their implications for cancer management will be discussed.

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“…On the other hand, chromosomal rearrangements between TMPRSS2 and ERG (TMPRSS2:ERG), made by AR binding to the “breakpoint ARE” in this region, occur in around 50% of prostate cancers [90,91,92,93]. Interestingly, Bowen et al [94] recently reported that NKX3-1 bound to the region adjacent to the “break point ARE” to prevent the TMPRSS2:ERG rearrangement and its expression.…”

Section: Ar Structure and Collaborating Factors In Ar Signaling Pamentioning

confidence: 99%

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

Obinata

Takayama

Takahashi

et al. 2017

Cancers

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Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer.

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NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

Cited by 33 publications

References 55 publications

Nkx3.1 controls the DNA repair response in the mouse prostate

Nkx3.1 controls the DNA repair response in the mouse prostate

Linking DNA Damage and Hormone Signaling Pathways in Cancer

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

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