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An in Vivo Screen Identifies PYGO2 As a Driver for Metastatic Prostate Cancer

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An in Vivo Screen Identifies PYGO2 As a Driver for Metastatic Prostate Cancer Published OnlineFirst May 16, 2018; DOI: 10.1158/0008-5472.CAN-17-3564 Cancer Molecular Cell Biology Research An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer Xin Lu1,2,3, Xiaolu Pan1, Chang-Jiun Wu4, Di Zhao1, Shan Feng2, Yong Zang5, Rumi Lee1, Sunada Khadka1, Samirkumar B. Amin4, Eun-Jung Jin6, Xiaoying Shang1, Pingna Deng1,Yanting Luo2,William R. Morgenlander2, Jacqueline Weinrich2, Xuemin Lu2, Shan Jiang7, Qing Chang7, Nora M. Navone8, Patricia Troncoso9, Ronald A. DePinho1, and Y. Alan Wang1 Abstract Advanced prostate cancer displays conspicuous chromosomal inhibits prostate cancer cell invasion in vitro and progression of instability and rampant copy number aberrations, yet the identity primary tumor and metastasis in vivo. In clinical samples, PYGO2 of functional drivers resident in many amplicons remain elusive. upregulation associated with higher Gleason score and metastasis Here, we implemented a functional genomics approach to identify to lymph nodes and bone. Silencing PYGO2 expression in patient- new oncogenes involved in prostate cancer progression. Through derived xenograft models impairs tumor progression. Finally, integrated analyses of focal amplicons in large prostate cancer PYGO2 is necessary to enhance the transcriptional activation in genomic and transcriptomic datasets as well as genes upregulated response to ligand-induced Wnt/b-catenin signaling. Together, our in metastasis, 276 putative oncogenes were enlisted into an in vivo results indicate that PYGO2 functions as a driver oncogene in the gain-of-function tumorigenesis screen. Among the top positive 1q21.3 amplicon and may serve as a potential prognostic bio- hits, we conducted an in-depth functional analysis on Pygopus marker and therapeutic target for metastatic prostate cancer. family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. Significance: Amplification/overexpression of PYGO2 may PYGO2 overexpression enhances primary tumor growth and local serve as a biomarker for prostate cancer progression and metas- invasion to draining lymph nodes. Conversely, PYGO2 depletion tasis. Cancer Res; 78(14); 3823–33. Ó2018 AACR. Introduction mutation frequency compared with most solid cancer types (8), yet advanced disease is characterized by rampant genomic Prostate cancer is the most commonly diagnosed noncuta- rearrangements and somatic copy number alterations (SCNA) neous malignancy and the third leading cause of cancer mor- (3–7). SCNAs affect a larger fraction of the cancer genome than tality for men in the United States (1). Bone is the most any other type of genetic alterations in cancer (9), underscoring frequent site for distant metastasis of prostate cancer, which the potential role of SCNAs in driving the malignant nature of inflicts significant morbidity and mortality (2). Genomic pro- prostate cancer. Functional driver genes residing within recur- filing of prostate cancer (3–7) has revealed overall lower rent amplifications include key prostate cancer oncogenes such as EZH2 on 7q36.1, MYC on 8q23-24, NCOA2 on 8q13.3, and 1Department of Cancer Biology, The University of Texas MD Anderson Cancer AR on Xq12 (3). Gain-of-function screens of resident genes Center, Houston, Texas. 2Department of Biological Sciences, Center for Rare and within amplicons are a proven approach in the identification of 3 Neglected Diseases, University of Notre Dame, Notre Dame, Indiana. Tumor novel oncogenes. Microenvironment and Metastasis Program, Indiana University Melvin and Bren In this study, our screen identified PYGO2 as a putative driver of Simon Cancer Center, Indianapolis, Indiana. 4Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5Depart- prostate cancer progression. PYGO2 is an essential transcription b ment of Biostatistics, Indiana University, Indianapolis, Indiana. 6Department of coactivator with -catenin/TCF complex for the Wnt signaling Biological Science, Wonkwang University, Cheonbuk, Iksan, South Korea. 7Insti- pathway in Drosophila (10). With a highly conserved plant home- tute for Applied Cancer Science, The University of Texas MD Anderson Cancer odomain (PHD) in its C-terminus, PYGO2 binds to H3K4me and 8 Center, Houston, Texas. Department of Genitourinary Medical Oncology, The activates b-catenin–dependent transcriptional regulation (11). 9 University of Texas MD Anderson Cancer Center, Houston, Texas. Department Evidence suggests that PYGO2 modulates gene transcription of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. through both Wnt-dependent and Wnt-independent mechanisms (11). Emerging data indicate its pivotal role in multiple cancers Note: Supplementary data for this article are available at Cancer Research including glioma (12), breast cancer (13), hepatic carcinoma Online (http://cancerres.aacrjournals.org/). (14), and intestinal tumors (15). Recently, PYGO2 expression X. Lu and X. Pan contributed equally to this article. was identified as a potential risk stratification marker for PSA Corresponding Authors: Ronald A. DePinho, University of Texas MD Anderson progression in prostate cancer following radical prostatectomy Cancer Center, 1881 East Road, Unit 1906, Houston TX 77054. Phone: 832-751- (16). PYGO2 is recruited by PCGEM1, a long noncoding RNA, to 9756; Fax: 713-745-7167; E-mail: [email protected]; and Y. Alan Wang, enhance AR-bound enhancer activity (17). Nevertheless, the [email protected] functional contribution of PYGO2 to prostate cancer progression, doi: 10.1158/0008-5472.CAN-17-3564 particularly bone metastasis, is not known, prompting us to Ó2018 American Association for Cancer Research. explore its role in prostate cancer biology. www.aacrjournals.org 3823 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 16, 2018; DOI: 10.1158/0008-5472.CAN-17-3564 Lu et al. Materials and Methods viruses individually and infected low-passage LHMK cells. Stable sublines were generated by blasticidin selection, with Cell culture and patient-derived xenograft models each subline individually expanded for the in vivo screen. The LHMK cell line was a generous gift from William Hahn (Dana-Farber Cancer Institute, Boston, MA; ref. 18). LHMK and 293T (obtained from ATCC) were maintained in DMEM, 10% In vivo ORF screen FBS. Prostate cancer cell lines PC-3, LNCaP, C4, C4-2, DU145, and To evaluate the tumorigenicity of the parental cell line, LHMK 22Rv1 were obtained from ATCC and maintained in RPMI640, cells were injected subcutaneously with 106 viable cells in a 10% FBS. L cells and L Wnt-3A cells were obtained from ATCC and mixture of PBS:Matrigel (BD Biosciences) in NCr nude mice maintained in DMEM, 10% FBS (for L Wnt-3A cells, 0.4 mg/mL (Taconic), which did not form tumors 6 months postimplanta- G-418 was supplemented). ATCC provides the Human STR tion. Expecting a small fraction of the candidate genes to pro- Profiling Cell Authentication Service to authenticate these cell mote tumorigenesis, we designed a multisite subcutaneous inoc- lines. All cells were routinely verified as being free of Mycoplasma ulation method to reduce the number of mice needed for the using MycoAlert Mycoplasma Detection Kit (Lonza). Patient- screen. For each LHMK-ORF subline, 106 viable cells, resus- derived xenograft (PDX) models were previously published and pended in 50 mL mixture of PBS:Matrigel, were injected subcu- generous gifts from N.M. Navone (19, 20). The scramble control taneously into prelabeled flank positions of mice (5 sites on each shRNA and PYGO2-targeting shRNA were ordered from Sigma, side of flank, so total 10 sites/mouse). The experiment was with sequences listed in Supplementary Table S1. designed so that each subline was evaluated in 10 different mice, and each mouse received injections from 10 different sublines. Generation of LHMK sublines for screening Mice were monitored for tumor formation via caliper measure- The opening reading frame (ORF) lentiviral vectors in the ment for 8 months. We did not observe formation of more than Precision LentiORF collection were obtained from the Func- two subcutaneous tumors on any mice in the screen. All animal tional Genomics Facility at MD Anderson Cancer Center experimental protocols were approved by the Institutional Ani- (Houston,TX).In96-wellplates,wepackaged288ORFlenti- mal Care and Use Committee at MD Anderson Cancer Center. Taylor et al. Grasso et al. Barbieri et al. TCGA 8 Oncomine transcriptome datasets Holzbeierlein et al. Focal peaks identified by GISTIC2.0 Lapointe et al. LaTulippe et al. 6,909 Amplified genes Vanaja et al. Varambally et al. Yu et al. Copy number correlated Taylor et al. Filter 1 Expression (P < 0.01) Grasso et al. 1018 Genes 25,484 Genes Metastasis > primary in ≥3/8 Metastasis > primary in ≥6/8 Filter 2 Oncomine datasets (P < 0.05) Oncomine datasets (P < 0.05) 394 Genes 363 Genes Ding et al. 741 Genes 77 Genes PB-Cre/Pten/p53/LSL-mTert model Precision In vivo LentiORF 288 ORFs Cross-species integrative analysis screen collection Figure 1. Oncogenomics-informed in vivo ORF screen. Three sources of candidate prostate cancer genes are integrated: 394 genes located in focal amplicons (4 genomics datasets) and expressed in correlation with copy number gain and metastasis phenotype (3/8 transcriptomic datasets); 363 genes upregulated in metastasis (6/8 transcriptomic datasets); and 77 genes from our published cross-species prostate cancer genome analysis (36). Among
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