BRD4 Regulates Metastatic Potential of Castration-Resistant Prostate Cancer through AHNAK

Abstract

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen deprivation therapy (ADT) and accumulated resistance strategies to evade androgen receptor (AR) suppression. In prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation, and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogeneous, ADT-resistant tumor. Here, we examined prostate cancer cell lines that model common castration-resistant prostate cancer (CRPC) subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and Extraterminal (BET) family of proteins. We found that BRD4 regulates cell migration across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate migration and invasion in less aggressive models that retain AR expression or signaling. BRD4, a coregulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits metastatic potential. Overall, these results reveal a novel BRD4-AHNAK pathway that may be targetable to treat metastatic CRPC (mCRPC).Implications: BRD4 functions as the dominant regulator of CRPC cell migration and invasion through direct transcriptional regulation of AHNAK, which together offer a novel targetable pathway to treat metastatic CRPC.

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…Among the various bromodomain regulators, particularly interesting id BRD4, an epigenetic reader protein in the BET family, which binds to enhancers and super-enhnacers of several genes involved in the control of cell proliferation and involved in tumor cell transcriptional addiction. Several observations support BRD4 as a potential therapeutic target in prostate cancer: (a) SPOP mutations impair ubiquitin-dependent proteasomal degradation of BRD4, upregulating BRD4 levels; (b) DUB3 deubiquitinates BRD4, increasing its levels and promoting prostate cancer progression [727]; (c) BRD4 impedes mitochondrial fission at the level of prostate cancer stem cells through induction of mitochondrial fission factor (MFF) [728]; and (d) BRD4 regulates metastatic potential of castration-resistant prostate cancer through AHNAK, a large scaffolding protein linked to promotion of metastasis [729]; BRD4 and ZFX modulate noncanonical oncogenic functions of the AR splice varian 7 in CRPC cells [730].…”

Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer

“…Remarkably, the activity of several upstream regulators playing an important role in prostate cancer development and progression have been predicted to be affected by SAB-13 ( Figure 5D). Among them, the following are suppressed: E2F3 (transcription factor, its activity was reported to be associated with poor prostate cancer patients treatment prognosis [35]), ADRB (β-adrenergic receptor, its signaling is involved in the development of aggressive prostate cancer [36]), BRD4 (kinase, associated with tumor growth and metastatic potential of prostate cancer [37,38]), 25s proteasome (a promising and relevant target in a number of human cancers including prostate cancer [39]), and MYC (proto-oncogene, is involved in initiation and progression of a number of human cancers [40] and drives the development of the highly aggressive neuroendocrine prostate cancer [36]) ( Figure 5D). Additionally, sirtuin and IL-8 signaling, as well as LXR/RXR and NO and ROS production in macrophages were proposed to be suppressed, while NER and EIF2 pathway, ILK signaling, and oxidative phosphorylation were predicted to be activated under the treatment ( Figure 5E).…”

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

“…The low level of relevant alterations in this case may explain his less aggressive disease course with a late clinical relapse (10 years post prostatectomy). The gains in BRD4 and AHNAK may have contributed to metastasis formation: BRD4, part of the Bromodomain and Extraterminal (BET) protein family, regulates tumour cell migration and invasion through transcription of AHNAK [83]. Small molecule BRD4-selective degraders inhibit metastatic potential in PCa cell lines and a Phase I clinical trial of birabresib which included CRPC patients has been completed [84].…”