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Balk, Steven

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Balk

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Steven

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Balk, Steven
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    Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma
    (Wiley, 2016-06-08) Gerrin, Sean J.; Sowalsky, Adam G.; Balk, Steven; Ye, Huihui
    INTRODUCTION—High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear. METHODS—We performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2:ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason pattern 3 and 4 foci, using microdissection and targeted deep-sequencing. RESULTS—A total of 32 tumor-specific mutated sites were successfully amplified and sequenced, including 25 truncal mutations and 7 mutations that were specific to either the Gp3 or Gp4 foci. All six HGPIN foci shared the same tumor-specific TMPRSS2:ERG fusion breakpoint, establishing that they were all clonally related to the adjacent invasive tumor. Among the 32 gene targets mutated in the invasive tumor, only mutation of the OR2AP1 gene, a truncal mutation, was found in a single focus of HGPIN. The remaining gene targets that were successfully sequenced were wild-type in all other HGPIN foci. DISCUSSION—This study demonstrates the feasibility of targeted mutation profiling of HGPIN lesions, which will be important to understand PCa tumorigenesis. The results in this case, showing a remarkable absence of truncal mutations in HGPIN lesions bearing the tumor-specific ERG fusion, indicate HGPIN lesions may be relatively stable genetically and argue against a stepwise clonal evolution model of HGPIN to PCa.
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    Calcium signaling: an underlying link between cardiac disease and carcinogenesis
    (BioMed Central, 2018) Xu, Xuehong; Balk, Steven; Isaacs, William B.; Ma, Jianjie
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    Androgen receptor functions in prostate cancer development and progression
    (Medknow Publications & Media Pvt Ltd, 2014) Balk, Steven
    The androgen receptor (AR) is critical for the normal development of prostate and for its differentiated functions. The consistent expression of AR in prostate cancer (PCa), and its continued activity in PCa that relapse after androgen deprivation therapy (castration-resistant prostate cancer (CRPC)), indicate that at least a subset of these genes are also critical for PCa development and progression. This review addressed AR regulated genes that may be critical for PCa, and how AR may acquire new functions during PCa development and progression.
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    Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer
    (Oxford University Press, 2017) Liu, Xiaming; Gao, Yanfei; Ye, Huihui; Gerrin, Sean; Ma, Fen; Wu, Yiming; Zhang, Tengfei; Russo, Joshua; Cai, Changmeng; Yuan, Xin; Liu, Jihong; Chen, Shaoyong; Balk, Steven
    Abstract P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.
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    Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation
    (Proceedings of the National Academy of Sciences, 2014) Hsieh, Chen-Lin; Fei, Teng; Chen, Yiwen; Li, Tiantian; Gao, Yanfei; Wang, Xiaodong; Sun, Tong; Sweeney, Christopher; Lee, Gwo-Shu Mary; Chen, Shaoyong; Balk, Steven; Liu, Xiaole; Brown, Myles; Kantoff, Philip
    The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer–promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 \((R^2 = 0.6213, P < 5 × 10^{−11})\) and KLK2 \((R^2 = 0.5893, P < 5 × 10^{−10})\) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.
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    Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation
    (Impact Journals LLC, 2016) Liu, Xiaming; Han, Weiwei; Gulla, Sarah; Simon, Nicholas I.; Gao, Yanfei; Cai, Changmeng; Yang, Hongmei; Zhang, Xiaoping; Liu, Jihong; Balk, Steven; Chen, Shaoyong
    The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4–2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).
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    Loss of Wave1 gene defines a subtype of lethal prostate cancer
    (Impact Journals LLC, 2015) Sowalsky, Adam G.; Sager, Rebecca; Schaefer, Rachel J.; Bratslavsky, Gennady; Pandolfi, Pier Paolo; Balk, Steven; Kotula, Leszek
    Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities.
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    Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
    (2016) Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K.; Balk, Steven; Taplin, Mary-Ellen; Auchus, Richard J.; Sharifi, Nima
    Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
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    Doxycycline Regulated Induction of AKT in Murine Prostate Drives Proliferation Independently of p27 Cyclin Dependent Kinase Inhibitor Downregulation
    (Public Library of Science, 2012) Wang, Hongyun; Xu, Youyuan; Fang, Zi; Chen, Sen; Balk, Steven; Yuan, Xin
    The PI3 kinase/AKT pathway has been shown to increase degradation of the p27 cyclin dependent kinase inhibitor through phosphorylation of consensus AKT sites on p27 and SKP2, and AKT driven proliferation may be checked by feedback mechanisms that increase p27 expression and induce senescence. However, these AKT sites are not conserved in mouse, and it has not been clear whether AKT negatively regulates murine p27. Transgenic mice with a probasin promoter controlled prostate specific reverse tetracycline transactivator (ARR2Pb-rtTA) were generated and used to achieve doxycycline inducible expression of a tetracycline operon regulated constitutively active myristoylated AKT1 transgene (tetO-myrAKT). Doxycycline induction of myrAKT occurred within 1 day and rapidly induced proliferation (within 4 days) and the development of prostatic intraepithelial neoplasia (PIN) lesions in ventral prostate, which did not progress to prostate cancer. Cells in these lesions expressed high levels of p27, had increased proliferation, and there was apoptosis of centrally located cells. Doxycycline withdrawal resulted in apoptosis of cells throughout the lesions and rapid clearing of hyperplastic glands, confirming in vivo the critical antiapoptotic functions of AKT. Significantly, analyses of prostates immediately after initiating doxycycline treatment further showed that p27 expression was rapidly increased, coincident with the induction of myrAKT and prior to the development of hyperplasia and PIN. These findings establish in vivo that murine p27 is not negatively regulated by AKT and indicate that proliferation in PI3 kinase/AKT pathway driven mouse models is mediated by p27 independent mechanisms that may be distinct from those in human. Further studies using prostate specific doxycycline regulated transgene expression may be useful to assess the acute effects of inducing additional transgenes in adult murine prostate epithelium, and to assess the requirements for continued transgene expression in transgene induced tumors.
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    Polycomb-independent activity of EZH2 in castration resistant prostate cancer
    (BioMed Central, 2013) Xu, Kexin; Wu, Zhenhua; Groner, Anna Claire; He, Housheng H; Cai, Changmeng; Stack, Edward C; Loda, Massimo; Liu, Tao; Morrissey, Colm; Vessella, Robert L; Kantoff, Philip; Balk, Steven; Liu, Xiaole; Brown, Myles