Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer

Nerlakanti, Niveditha; Yao, Jiqiang; Nguyen, Duy T.; Patel, Asmita; Eroshkin, Alexey; Lawrence, Harshani R.; Ayaz, Muhammad; Kuenzi, Brent M.; Agarwal, Neha; Chen, Yunyun; Gunawan, Steven; Karim, Rezaul M.; Berndt, Norbert; Puskas, John; Magliocco, Anthony M.; Coppola, Domenico; Dhillon, Jasreman; Zhang, Jingsong; Shymalagovindarajan, Subramaniam; Rix, Uwe; Kim, Young‐Chul; Perera, Ranjan J.; Schönbrunn, E.; Mahajan, Kiran

doi:10.1158/1535-7163.mct-18-0602

Cited by 28 publications

(42 citation statements)

References 43 publications

(62 reference statements)

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“…Mechanistically, ACK1 modulates AR gene expression through epigenetic regulation ( 27 ), and its androgen-independent activity through tyrosine phosphorylation ( 23 , 31 , 32 ) and interaction with co-regulators ( 33 ). In contrast, HOXB13 regulates AR expression and function, as well as AR and AR-V7 chromatin binding in mCRPCs ( 29 , 34 ). Thus, targeting this axis is critical to suppress CRPC recurrence.…”

Section: Ack1–ar–hoxb13 Axismentioning

confidence: 98%

“…In normal cells, AR activity is exquisitely regulated through limited expression, cytosolic localization and association with protein complexes ( 40 ). In contrast, AR is overexpressed ( 41–43 ) or functionally activated in most PCs through a variety of mechanisms ( 24 ), such as gene body amplification ( 44–46 ), AR distal enhancer amplification ( 44 , 45 , 47 ), increased histone acetylation/phosphorylation at AR enhancers ( 27 , 48 , 49 ), overexpression of its co-regulators ( 29 , 30 , 43 ) and protein-stabilizing post-translational modifications ( 23 , 50–52 ). AR deregulation ultimately leads to increased pathologically active AR at tumor-specific AR-binding sites, an outcome correlating with PC progression ( 27 , 53 , 54 ).…”

Section: Ar In Crpc Pathophysiologymentioning

confidence: 99%

“…These epigenetic alterations include removal of repressive histone H3 lysine 9 me2/3 methylation (H3K9me2/3) by the AR interacting histone demethylases KDM1A and KDM3A ( 61–64 ) or increased histone H3K27 acetylation by CBP/p300, thus promoting expression of a subset of AR target genes ( 50 , 58–60 ). Whereas the BRD inhibitor JQ1 ( 29 , 55 , 56 ) and the p300/CBP inhibitors A485 and GNE-049 ( 65 , 66 ) suppress AR target gene expression and inhibit prostate xenograft tumor growth, their broad epigenetic substrate activity has limited their potential clinical use. Consequently, the identification of more targeted approaches and therapeutic vulnerabilities in CRPC is being pursued.…”

Section: Ar In Crpc Pathophysiologymentioning

confidence: 99%

“…Therefore, to activate developmental genes such as HOXB13 with hypermethylated CpG islands, a three-step process is required: (i) DNA demethylation; (ii) removal of the repressive H3K27me3 marks ( 96 ); and (iii) their replacement with activating histone acetylation marks. Recent studies have revealed enrichment in H3K27 acetylation as well as H4K5 and K8 acetylation at the HOXB13 promoter-proximal region in CRPC ( 29 ). Moreover, treatment with GSK126, a PRC2 catalytic inhibitor of H3K27me3, does not affect HOXB13 expression in CRPC cell line C4-2B indicating a state of constitutive activation ( 29 ).…”

Section: Epigenetic Regulation Of Hoxb13 a Pc Rimentioning

confidence: 99%

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ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

et al. 2020

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The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)-9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR–ACK1 and AR–HOXB13 pathways as key mediators of CRPC recurrence.

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Section: Ack1–ar–hoxb13 Axismentioning

confidence: 98%

Section: Ar In Crpc Pathophysiologymentioning

confidence: 99%

Section: Ar In Crpc Pathophysiologymentioning

confidence: 99%

Section: Epigenetic Regulation Of Hoxb13 a Pc Rimentioning

confidence: 99%

See 2 more Smart Citations

ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

et al. 2020

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“…Re-wiring of TFs changes the consequences of cell signaling and contributes to changes in lineage plasticity that are also associated with aggressive PCa 25 – 27 . Therefore understanding how TF signaling occurs in PCa progression can lead to the development of strategies for targeting these changes through targeted epigenetic therapies 28 – 30 , or the downstream gene networks may be uniquely drug-sensitive 31 , 32 . Furthermore disease-specific enhancers that are newly activated provide rationale for targeted deep sequencing to dissect the interactions of germline and structural variation at tumor-driving enhancers 33 , 34 .…”

Section: Introductionmentioning

confidence: 99%

Identification of transcription factor co-regulators that drive prostate cancer progression

Siddappa

Wani

Long

et al. 2020

Sci Rep

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In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

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Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

et al. 2022

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In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens.Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option.Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.

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Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer

Cited by 28 publications

References 43 publications

ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

Identification of transcription factor co-regulators that drive prostate cancer progression

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

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