Neuroendocrine differentiation in prostate cancer: key epigenetic players

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1 Editorial Neuroendocrine differentiation in rostate cancer: key eigenetic layers Karishma Guta 1,2, Sanjay Guta 1,2,3,4,5 1 Deartment of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; 2 The Urology Institute, University Hositals Cleveland Medical Center, Cleveland, OH, USA; 3 Deartment of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA; 4 Deartment of Nutrition, Case Western Reserve University, Cleveland, OH, USA; 5 Division of General Medical Sciences, Case Comrehensive Cancer Center, Cleveland, OH, USA Corresondence to: Sanjay Guta, hd. Deartment of Urology, Case Western Reserve University, Euclid Avenue, Cleveland, Ohio 44106, USA. sanjay.guta@case.edu. rovenance: This is an invited Editorial commissioned by Section Editor Lichao Sun [State Key Laboratory of Molecular Oncology, National Cancer Center (NCC)/Cancer Hosital, Chinese Academy of Medical Sciences (CAMS), eking Union Medical College, Beijing, China]. Comment on: Dardenne E, Beltran H, Benelli M, et al. Induces an EZH2-Mediated Transcritional rogram Driving Neuroendocrine rostate Cancer. Cancer Cell 2016;30: Submitted Dec 07, Acceted for ublication Dec 23, doi: /tcr View this article at: htt://dx.doi.org/ /tcr A recent ublication by Dardenne et al. (1) in Cancer Cell (October 10, Vol. 30: , 2016) demonstrate overexression and its stabilization by Aurora-A (AURKA) and AKT1 Kinase induces enhancer of zeste homolog 2 (EZH2)-mediated transcritional rerogramming reressing androgen recetor (AR) and driving neuroendocrine rostate cancer (1). This has imortant clinical imlication roosing combinatorial theray using inhibitors of hoshatidylinositol 3-kinase (I3K)-AKT and AURKA as future trials in the management of neuroendocrine tumors. Neuroendocrine differentiation in rostate cancer (NEC) is frequently associated with advance disease and oor clinical outcome (2,3). The incidence of neuroendocrine henotyes in rimary rostate cancers is aroximately 1% whereas in lethal metastatic castrateresistant rostate cancers its ercentage is u to 25 30% (4). Emerging evidence suggests that NEC develos as a transdifferentiation from rostate adenocarcinoma, in resonse to androgen derivation theray and/or treatment with inhibitors targeting AR signaling athways (5). During NEC develoment, cells lose their granular structure and demonstrate small cell neuroendocrinelike morhology, ositive for tyical neuroendocrine markers such as chromogranins, synatohysin (SY), and neurosecific enolase (NSE) but little or very low levels of AR and AR-regulated gene exression (6). Since AR signaling is required for eithelial cell differentiation during rostate develoment, inhibition of AR athway likely initiates develomental rerogramming of rostate adenocarcinoma to neuroendocrine tumors through a transdifferentiation mechanism (7). Unlike rostate adenocarcinoma, neuroendocrine tumors are very aggressive with median cancer-secific survival is less than 2 years (8). Conventionally, neuroendocrine rostate cancers have been managed clinically with cislatin-based chemotheray regimens, however further identification and understanding of the oncogenic drivers of this henotye necessitates the develoment of novel targeted theraies. Dardenne et al. (1) erformed an integrated analysis emloying clinical rostate cancer secimens consisting of NEC tumor cells and castrate-resistant rostate tumors with focal neuroendocrine differentiation, which correlated higher exression in the neuroendocrine henotye. In arallel studies, authors generated genetically-engineered mouse (GEM) model that harbor a CAG-driven loxsto-lox human MYCN gene integrated into the ROSA26 (LSL-MYCN) locus and a Tmrss2-driven tamoxifenactivated Cre recombinase. T2-Cre secifically mediates Cre recombination in luminal cells in the rostate. These mice were cross-bred with other mice that harbor a ten Translational Cancer Research. All rights reserved. tcr.amegrous.com Transl Cancer Res 2017;6(Sul 1):S104-S108

2 Translational Cancer Research, Vol 6, Sul 1 February 2017 conditional knockout allele leading to increase in I3K/ AKT signaling enhancing rotein stability. Mice with heterozygous loss of ten and overexression exhibited a divergent mixture of large invasive carcinoma in the rostate with foci containing AR-ositive adenocarcinoma or AR-negative NEC tumor cells, comared with the corresonding control. The NEC foci dislayed high levels of MYCN RNA with overexression associated with enhanced AKT signaling. In another study, Lee et al. (9) using a model of remalignant rostatic intraeithelial neolasia demonstrated that active myristoylated AKT1 together with forced exression of MYCN in normal rostate basal cells (but not in luminal cells) led to the develoment of invasive, metastatic castration-resistant tumors ositive for neuroendocrine markers. Furthermore, NEC tumors with overexression abrogates AR signaling and downregulates AR-target gene FKB5, a member of the immunohilin rotein family, which serves as a scaffolding rotein for AKT and HL romoting HL dehoshorylation of AKT at amino acid S473 (-AKT). FKB5 downregulation leads to activation of AKT by releasing FKB5-HLmediated suression of AKT in the crosstalk between AR signaling and I3K-AKT athway. Based on the results, the current study establishes the oncogenic role of MYCN in neuroendocrine rostate cancer. Several ublished studies have demonstrated the oncogenic role of various genes that likely facilitate the rogression of rostate adenocarcinoma to NEC through AR suression (5,7), involvement of AR-slice variants (10), and induction of neuroendocrine features and neural rograms (11). Many genes associated with a neuroendocrine henotye, include AR-regulated genes viz. ARG2 (12) and hash-1 (13). Additional drivers in the athogenesis of NEC include loss of tumor suressors, activation of mitotic rograms, and genomic instability. Tumor suressors T53 and RB1 are dysfunctional in various malignancies including NEC (14,15). The combined deficiency of RB1 and T53 romotes the transformation to NEC, as reorted in conditional mouse models of NEC (16). Besides, several cell-cycle genes have been shown to be frequently amlified and/or overexressed in NEC, thus suorting their role in driving uncontrolled NEC growth and roliferation. This list includes UBE2C, cyclin D1, Src family kinase- FYN, and olo-like kinase LK1 (17-19). The most noteworthy observation of the study involves binding of to AR enhancers and the subsequent interaction of this comlex with the members of olycomb S105 reressive comlex 2 (RC2). The olycomb grou roteins EZH2, suressor of zeste 12 (SUZ12), embryonic ectoderm develoment (EED), and RbA48 form the RC2 comlex, which secifically trimethylates lysine-27 of histone H3 (H3K27) on target gene romoters (20). This histone marker is art of a rerogrammed cellular memory system inherited through mitotic cell divisions and thus reserves cellular identity. Genome-wide location analysis revealed that RC2 reresses a secial set of develomental regulators and signaling molecules. Notably, EZH2 is the catalytic subunit of RC2 and is a highly conserved histone methyltransferase (HMT) that targets H3K27 trimethylation. This trimethylated H3K27 chromatin is commonly associated with silencing of differentiation genes in humans (21). Current study reveals that the catalytic activity of EZH2 facilitates /AR/EZH2-RC2 comlex formation. High levels of EZH2 rotein and its activity in the rostate of mice overexressing redirects EZH2 activity to target gene romoters resulting in transcrition reression, whereas EZH2 inhibition reverses gene regulation (1). Thus, the interaction between, AR, and EZH2 results in the abrogation of AR signaling desite abundant levels of AR, suggesting that the amlification of MYCN and inactivation of AR might be a significant henomenon in NEC tumors (Figure 1). Moreover, RE1-silencing transcrition factor (REST) is another eigenetic alteration essential in driving the develoment of the NE henotye, which is controlled by AR (22). In addition to these eigenetic modifications, several novel somatic mutations in multile chromatin/ histone modifiers including MLL2, UTX and ASXL1 as well as transcrition factors FOXA1 and ETS2 were noted in neuroendocrine rostate tumors (23). Using cell culture and re-clinical mouse models, the authors further demonstrate that forms a comlex with AURKA that results in stabilization in NEC tumors. Aurora kinases (A and B), comosed of serine/ threonine kinase, are essential for cell roliferation. Secifically, AURKA amlification has been reorted in over 60% of rostate cancer from atients that develoed treatment-related NEC and in 86% of metastases, whereas concurrent amlification of was resent in 69% of treated rostate cancer and 83% of metastases (24). In the exeriments, harmacological inhibition of allosteric AURKA inhibitor led to raid dissociation of the - AURKA comlex and raid degradation of. In accordance with these findings, Lee et al. (9) evaluated the theraeutic efficacy of several AURKA inhibitors and Translational Cancer Research. All rights reserved. tcr.amegrous.com Transl Cancer Res 2017;6(Sul 1):S104-S108

3 S106 Guta and Guta. Oncogenic drivers of neuroendocrine rostate cancer lasma membrane Recetor tyrosine kinase I2 I3 AURKA I3K AKT Degradation inhibited TEN Nucleus Castration resistant rostate cancer Co-regulator/ Co-reressor comlex AR AR EZH2 AR Target genes (SA, NKX3.1 KLK3 etc.) Androgen resonse elements (ARE) Neuroendocrine markers (CgA, SY, NSE etc.) Neuroendocrine differentiation Figure 1 Schematic model of neuroendocrine differentiation in rostate cancer. is overexressed after first-line or second-line androgen derivation theray. AURKA can bind and stabilize in the cytosol. In the model, signaling is initiated at the membrane with recetor tyrosine kinases (RTKs) which are activated in ligand-secific manner. RTK activates I3K through conversion by its catalytic domain of hoshatidylinositol (3,4)-bis-hoshate (I2) liids to hoshatidylinositol (3,4,5)-tris-hoshate (I3) where hoshatase and tensin homolog (TEN), a tumor suressor liid hoshatase, converts it back to I2. TEN is frequently mutated or deleted in castrateresistant rostate cancer and its loss constitutively activates Akt, which in turn hoshorylates. hoshorylated translocates to the nucleus, hysically binds and forms a comlex with EZH2, a catalytic subunit of RC2 comlex and abrogates AR from its binding to androgen-resonse elements (ARE). The interaction between, AR, and EZH2 results in the abrogation of AR signaling, desite abundant levels of AR, reresses AR targeted genes viz. rostate-secific antigen (SA), KLK3 and NKX3.1. Notably, MYCN amlification serves an oncogenic driver in driving neuroendocrine differentiation in rostate cancer cells recognized by exression of neuroendocrine markers such as chromogranin A (CgA), SY, and NSE. AR, androgen recetor; SY, synatohysin; NSE, neurosecific enolase. found that CD532, a novel AURKA inhibitor, results in a significant reduction in MYCN rotein levels and decreased tumor burden in re-clinical models driven by MYCN overexression. Interestingly, this effect was not observed with MLN8237 an AURKA inhibitor, which is currently in early-hase clinical trials, as downregulation of MYCN rotein levels did not aear to be deendent on AURKA kinase activity. However, the resent study findings demonstrate that overexressing cells exhibit higher sensitivity to AKT inhibitors in combination with allosteric AURKA inhibitor. Clinical and genomic rofiling data roose that neuroendocrine rostate cancers may originate de novo from a small oulation of neuroendocrine cells resent in the rostate (2-4). However in the majority of cases these tumors diverge from a oulation of luminal-derived metastatic castrate-resistant adenocarcinoma. Either way, these two rocesses are referentially mobilized under selective ressure from castration and/or treatment with AR inhibitors in conjunction with genetic erturbations that hel initiate or maintain NE henotye. While the current study establishes the oncogenic role of in NEC, it is still unclear the recise cell of origin of NEC and their maintenance in vivo. It is ostulated that the stimulation of growth factor roduction, such as eidermal growth factor, insulin-like growth factor, keratinocyte growth factor and secretion of some ro-inflammatory cytokines including interleukin: IL-6, IL-8, IL-1β and macrohage migration inhibitory factor can romote neuroendocrine differentiation through AR athway in the absence of androgens (25). The significance of this manuscrit lies in its ability to Translational Cancer Research. All rights reserved. tcr.amegrous.com Transl Cancer Res 2017;6(Sul 1):S104-S108

4 Translational Cancer Research, Vol 6, Sul 1 February 2017 S107 demonstrate the cooeration between and EZH2 in reressing AR to drive NEC. This has imortant clinical imlication and rationale for combining theray targeting or co-targeting molecules in driven tumors through newly designed clinical trials in future. Acknowledgements Funding: This work was suorted by VA Merit Review 1I01BX and the United States ublic Health Service Grants RO1CA108512, R21CA and R03CA to S Guta. Footnote Conflicts of Interest: The authors have no conflicts of interest to declare. References 1. Dardenne E, Beltran H, Benelli M, et al. Induces an EZH2-Mediated Transcritional rogram Driving Neuroendocrine rostate Cancer. Cancer Cell 2016;30: Santoni M, Conti A, Burattini L, et al. Neuroendocrine differentiation in rostate cancer: novel morhological insights and future theraeutic ersectives. Biochim Biohys Acta 2014;1846: Grigore AD, Ben-Jacob E, Farach-Carson MC. rostate cancer and neuroendocrine differentiation: more neuronal, less endocrine? Front Oncol 2015;5: Estein JI, Amin MB, Beltran H, et al. roosed morhologic classification of rostate cancer with neuroendocrine differentiation. Am J Surg athol 2014;38: Liianskaya J, Cohen A, Chen CJ, et al. Androgenderivation theray-induced aggressive rostate cancer with neuroendocrine differentiation. Asian J Androl 2014;16: Ather MH, Abbas F, Faruqui N, et al. Correlation of three immunohistochemically detected markers of neuroendocrine differentiation with clinical redictors of disease rogression in rostate cancer. BMC Urol 2008;8: Komiya A, Yasuda K, Watanabe A, et al. The rognostic significance of loss of the androgen recetor and neuroendocrine differentiation in rostate biosy secimens among castration-resistant rostate cancer atients. Mol Clin Oncol 2013;1: Bostwick DG, Qian J, acelli A, et al. Neuroendocrine exression in node ositive rostate cancer: correlation with systemic rogression and atient survival. J Urol 2002;168: Lee JK, hillis JW, Smith BA, et al. Drives Neuroendocrine rostate Cancer Initiated from Human rostate Eithelial Cells. Cancer Cell 2016;29: Qiao J, Grabowska MM, Forestier-Roman IS, et al. Activation of GR/GR-R signaling contributes to castration-resistant rostate cancer rogression. Oncotarget 2016;7: Bisho JL, Thaer D, Vahid S, et al. The Master Neural Transcrition Factor BRN2 Is an Androgen Recetor- Suressed Driver of Neuroendocrine Differentiation in rostate Cancer. Cancer Discov 2017;7: Gannon O, Godin-Ethier J, Hassler M, et al. Androgenregulated exression of arginase 1, arginase 2 and interleukin-8 in human rostate cancer. LoS One 2010;5:e Raa I, Volante M, Migliore C, et al. Human ASH-1 romotes neuroendocrine differentiation in androgen derivation conditions and interferes with androgen resonsiveness in rostate cancer cells. rostate 2013;73: Tan HL, Sood A, Rahimi HA, et al. Rb loss is characteristic of rostatic small cell neuroendocrine carcinoma. Clin Cancer Res 2014;20: Hansel DE, Nakayama M, Luo J, et al. Shared T53 gene mutation in morhologically and henotyically distinct concurrent rimary small cell neuroendocrine carcinoma and adenocarcinoma of the rostate. rostate 2009;69: Akamatsu S, Wyatt AW, Lin D, et al. The lacental Gene EG10 romotes rogression of Neuroendocrine rostate Cancer. Cell Re 2015;12: ernicová Z, Slabáková E, Fedr R, et al. The role of high cell density in the romotion of neuroendocrine transdifferentiation of rostate cancer cells. Mol Cancer 2014;13: Gururajan M, Cavassani KA, Sievert M, et al. SRC family kinase FYN romotes the neuroendocrine henotye and visceral metastasis in advanced rostate cancer. Oncotarget 2015;6: Grobholz R, Griebe M, Sauer CG, et al. Influence of neuroendocrine tumor cells on roliferation in rostatic carcinoma. Hum athol 2005;36: Clermont L, Lin D, Crea F, et al. olycomb-mediated Translational Cancer Research. All rights reserved. tcr.amegrous.com Transl Cancer Res 2017;6(Sul 1):S104-S108

5 S108 Guta and Guta. Oncogenic drivers of neuroendocrine rostate cancer silencing in neuroendocrine rostate cancer. Clin Eigenetics 2015;7: Deb G, Singh AK, Guta S. EZH2: not EZHY (easy) to deal. Mol Cancer Res 2014;12: Svensson C, Ceder J, Iglesias-Gato D, et al. REST mediates androgen recetor actions on gene reression and redicts early recurrence of rostate cancer. Nucleic Acids Res 2014;42: Guta S, Li J, Kemeny G, et al. Whole Genomic Coy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant rostate Cancer. Clin Cancer Res [Eub ahead of rint]. 24. Beltran H, Rickman DS, ark K, et al. Molecular characterization of neuroendocrine rostate cancer and identification of new drug targets. Cancer Discov 2011;1: Yuan TC, Veeramani S, Lin MF. Neuroendocrine-like rostate cancer cells: neuroendocrine transdifferentiation of rostate adenocarcinoma cells. Endocr Relat Cancer 2007;14: Cite this article as: Guta K, Guta S. Neuroendocrine differentiation in rostate cancer: key eigenetic layers. Transl Cancer Res 2017;6(Sul 1):S104-S108. doi: / tcr Translational Cancer Research. All rights reserved. tcr.amegrous.com Transl Cancer Res 2017;6(Sul 1):S104-S108