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Heterochromatin Protein 1A Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer Xinpei Ci1,2, Jun Hao1,2, Xin Dong2, Stephen Y

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Heterochromatin Protein 1A Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer Xinpei Ci1,2, Jun Hao1,2, Xin Dong2, Stephen Y Published OnlineFirst February 27, 2018; DOI: 10.1158/0008-5472.CAN-17-3677 Cancer Tumor Biology and Immunology Research Heterochromatin Protein 1a Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer Xinpei Ci1,2, Jun Hao1,2, Xin Dong2, Stephen Y. Choi1,2, Hui Xue2, Rebecca Wu2, Sifeng Qu1,2, Peter W. Gout2, Fang Zhang2, Anne M. Haegert1, Ladan Fazli1, Francesco Crea3, Christopher J. Ong1, Amina Zoubeidi1, Housheng H. He4,5, Martin E. Gleave1, Colin C. Collins1, Dong Lin1,2, and Yuzhuo Wang1,2 Abstract Neuroendocrine prostate cancer (NEPC) is a lethal subtype NEPC samples. HP1a knockdown in the NCI-H660 NEPC cell of prostate cancer arising mostly from adenocarcinoma via line inhibited proliferation, ablated colony formation, and neuroendocrine transdifferentiation following androgen dep- induced apoptotic cell death, ultimately leading to tumor rivation therapy. Mechanisms contributing to both NEPC growth arrest. Its ectopic expression significantly promoted development and its aggressiveness remain elusive. In light of NE transdifferentiation in adenocarcinoma cells subjected to the fact that hyperchromatic nuclei are a distinguishing histo- androgen deprivation treatment. Mechanistically, HP1a pathologic feature of NEPC, we utilized transcriptomic anal- reduced expression of androgen receptor and RE1 silencing yses of our patient-derived xenograft (PDX) models, multiple transcription factor and enriched the repressive trimethylated clinical cohorts, and genetically engineered mouse models to histone H3 at Lys9 mark on their respective gene promoters. identify 36 heterochromatin-related genes that are significantly These observations indicate a novel mechanism underlying enriched in NEPC. Longitudinal analysis using our unique, NEPC development mediated by abnormally expressed hetero- first-in-field PDX model of adenocarcinoma-to-NEPC transdif- chromatin genes, with HP1a as an early functional mediator ferentiation revealed that, among those 36 heterochromatin- and a potential therapeutic target for NEPC prevention and related genes, heterochromatin protein 1a (HP1a) expression management. increased early and steadily during NEPC development and Significance: Heterochromatin proteins play a fundamental remained elevated in the developed NEPC tumor. Its elevated role in NEPC, illuminating new therapeutic targets for this aggres- expression was further confirmed in multiple PDX and clinical sive disease. Cancer Res; 78(10); 2691–704. Ó2018 AACR. Introduction androgen deprivation treatment (ADT), resisting dependence on AR signaling as an adaptive response. As next-generation AR Neuroendocrine prostate cancer (NEPC) has become a clinical pathway inhibitors (ARPI) such as enzalutamide (EnZ) and challenge in the management of castration-resistant prostate abiraterone have made substantial improvements in managing cancer (CRPC). Although de novo cases are rare, NEPC as a special CRPC adenocarcinomas in recent years (1), it is expected that the subtype of CRPC (10%–20%) is thought to occur via NE incidence of NEPC will further increase (2). Unfortunately, the transdifferentiation of prostate adenocarcinomas in response to overall median survival of NEPC with small cell feature is less than 1 year, primarily due to its aggressiveness and limited available treatment options (3). As such, a better understanding of the 1 Vancouver Prostate Centre, Department of Urologic Sciences, University of mechanisms underlying NEPC development remains much need- 2 British Columbia, Vancouver, British Columbia, Canada. Department of Exper- ed in order to develop more effective therapeutics. imental Therapeutics, BC Cancer, Vancouver, British Columbia, Canada. 3School of Life, Health and Chemical Sciences, the Open University, Walton Hall, Milton One distinct histopathologic feature of NEPC cells is the fi Keynes, United Kingdom. 4Princess Margaret Cancer Center, University Health frequent manifestation of hyperchromatic nuclei with nely Network, Toronto, Ontario, Canada. 5Department of Medical Biophysics, Uni- dispersed chromatin and inconspicuous nucleoli, a phenomenon versity of Toronto, Toronto, Ontario, Canada. known as "salt and pepper" chromatin (3, 4). This is in contrast to Note: Supplementary data for this article are available at Cancer Research prostatic adenocarcinoma cells, which tend to have enlarged Online (http://cancerres.aacrjournals.org/). nuclei with prominent nucleoli (3, 4). This special hematoxy- Corresponding Authors: Yuzhuo Wang, BC Cancer/UBC, 675 W. 10th Ave., lin-staining characteristic suggests a distinct NEPC heterochro- Vancouver, BC V5Z 1L3, Canada. Phone: 604-675-8013; Fax: 604-675-8019; matin pattern (5). Heterochromatin is a condensed and transcrip- E-mail: [email protected]; and Dong Lin, Vancouver Prostate Centre, Department tionally inert chromosome conformation, regulated epigenetical- of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancou- ly by precise and dedicated machineries (6, 7). Multiple studies ver, BC V6H3Z6, Canada. Phone: 604-675-7013; E-mail: have demonstrated that epigenetic regulation is one major mech- [email protected] anism underlying NEPC development (8–11). An NEPC-specific doi: 10.1158/0008-5472.CAN-17-3677 heterochromatin gene signature can thus shed light to help better Ó2018 American Association for Cancer Research. understand the disease and identify novel therapeutic targets. www.aacrjournals.org 2691 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst February 27, 2018; DOI: 10.1158/0008-5472.CAN-17-3677 Ci et al. Another distinct feature of NEPC is the lineage alteration associ- the repressive histone mark H3K9me3 on their respective gene ated with a decrease or loss of crucial adenocarcinoma lineage– promoters. specific transcription factors, AR, FOXA1, and RE1 silencing transcription factor (REST; refs. 12–15). This leads to the repres- Materials and Methods sion of AR-regulated genes (e.g., prostate-specific antigen) and PDXs and clinical datasets gain of neuroendocrine markers [e.g., neural cell adhesion mol- All PDX tumor lines were grafted in NSG mice as previously ecule 1 (NCAM1/CD56), neuronal-specific enolase (NSE), chro- described (21). This study followed the ethical guidelines stated in mogranin A (CHGA), and synaptophysin (SYP); refs. 12–14]. the Declaration of Helsinki, specimens were obtained from Although recent studies have reported that EZH2 inhibits AR patients with their informed written consent form following a expression and SRRM4 mediates REST splicing (8, 16), the protocol (#H09-01628) approved by the Institutional Review mechanisms underlying the constant transcriptional suppression Board of the University of British Columbia (UBC). Animal of AR and REST are still not well understood. studies under the protocol #A17-0165 were approved by UBC's One of the major hurdles in studying NEPC is the lack of Animal Care and Use Committee. The LTL331-castrated tissues clinically relevant models, but substantial progress has been and the NEPC-relapsed LTL331R tissues were harvested at differ- achieved recently in modeling NEPC development. Employing ent time points after host castration (22). Transcriptomic analysis genetically engineered mouse (GEM) models, ectopic gain of for all PDX tumors, with the exception of the LTL331-331R N-myc and concomitant loss of Rb1 and Tp53 have both been castration time-series samples, was performed using GE 8 Â demonstrated to induce de novo NEPC-like tumors (8, 11). 60K microarray, as previously described (21). Transcriptomic Potent ADT using abiraterone in Tp53/Pten double-deficient analysis of the LTL331-331R time-series was done using RNA- mice also promoted overt neuroendocrine (NE) transdifferen- sequencing data. tiation of luminal adenocarcinoma cells (17). Employing engi- The clinical cohorts used in this study are as follows: RNA-seq neered human primary cells or cell lines, N-myc, SOX2, BRN2, data for the Beltran 2011 cohort (30 adenocarcinomas, 6 NEPCs) and SRRM4 overexpressions have all been shown to promote were from Weill Medical College of Cornell University (23); RNA- NE transdifferentiation (16, 18–20). Our laboratory has estab- Seq data for the Beltran 2016 (34 CRPC-adenocarcinomas, 15 lished over 45 high-fidelity patient-derived xenograft (PDX) NEPCs), the Grasso 2012 (31 CRPC-adenocarcinomas, 4 NEPCs), models of prostate cancer including 5 NEPCs (www.livingtu and the Kumar 2016 (149 CRPC-adenocarcinomas) cohorts were morlab.ca; ref. 21). Among them, LTL331/331R is the first-in- accessed through the cBioPortal (10, 24–26); microarray data for field and unique PDX model of adenocarcinoma-to-NEPC the Varambally 2015 cohort (6 CRPC-adenocarcinomas) were transdifferentiation. Upon host castration, the primary adeno- accessed from the Gene Expression Omnibus (GEO) database carcinoma (LTL331) initially regresses but relapses within few (GSE3325; ref. 27). months as typical NEPC (LTL331R; ref. 21). Importantly, the whole transdifferentiation process observed in the LTL331/ 331R model is predictive of disease progression and is fully Human prostate cancer specimens recapitulated in the donor patient (22), suggesting a strong Prostate cancer specimens were obtained from the Vancouver clinical relevance. Because an overwhelming majority of Prostate Centre Tissue Bank (103 hormone-na€ve primary pros- expressed genes accounting for the NE phenotype in terminal tatic adenocarcinomas, 120 CRPC-adenocarcinomas,
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