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Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion Yinhui Yang1,2, Alexandra M

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Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion Yinhui Yang1,2, Alexandra M Published OnlineFirst October 6, 2017; DOI: 10.1158/0008-5472.CAN-17-0686 Cancer Molecular and Cellular Pathobiology Research Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion Yinhui Yang1,2, Alexandra M. Blee2, Dejie Wang2, Jian An2, Yunqian Pan2, Yuqian Yan2, Tao Ma2, Yundong He2, Joseph Dugdale2, Xiaonan Hou3, Jun Zhang4, S. John Weroha3, Wei-Guo Zhu5, Y. Alan Wang6, Ronald A. DePinho6, Wanhai Xu1, and Haojie Huang2,7,8 Abstract E26 transformation-specific transcription factor ERG is aber- Patient specimen analysis demonstrated that FOXO1 and ERG rantly overexpressed in approximately 50% of all human prostate protein expression inversely correlated in a subset of human cancer due to TMPRSS2-ERG gene rearrangements. However, mice prostate cancer. Although human ERG transgene expression or with prostate-specific transgenic expression of prostate cancer– homozygous deletion of Foxo1 alone in the mouse prostate failed associated ERG alone fail to develop prostate cancer, highlighting to promote tumorigenesis, concomitant ERG transgene expres- that ERG requires other lesions to drive prostate tumorigenesis. sion and Foxo1 deletion resulted in upregulation of ERG target Forkhead box (FOXO) transcription factor FOXO1 is a tumor genes, increased cell proliferation, and formation of high-grade suppressor that is frequently inactivated in human prostate can- prostatic intraepithelial neoplasia. Overall, we provide biochem- cer. Here, we demonstrate that FOXO1, but not other FOXO ical and genetic evidence that aberrantly activated ERG cooperates proteins (FOXO3 and FOXO4), binds and inhibits the transcrip- with FOXO1 deficiency to promote prostate tumorigenesis and tional activity of prostate cancer–associated ERG independently cell invasion. Our findings enhance understanding of prostate of FOXO1 transcriptional activity. Knockdown of endogenous cancer etiology and suggest that the FOXO1–ERG signaling axis FOXO1 increased invasion of TMPRSS2–ERG fusion–positive can be a potential target for treatment of prostate cancer. Cancer Res; VCaP cells, an effect completely abolished by ERG knockdown. 77(23); 6524–37. Ó2017 AACR. Introduction alterations detected in human prostate cancer specimens has not been rigorously examined in cell culture systems and mouse Prostate cancer is the most commonly diagnosed cancer and the models. third leading cause of cancer death in American men (1). Multiple TMPRSS2–ERG gene rearrangements are one of the most fre- genetic alterations including gene mutations, deletions, and quent genetic alterations detected in human primary prostate amplifications have been revealed by next-generation high- cancer (2, 4). ERG is an oncogenic protein that belongs to the throughput sequencing in both primary and advanced prostate E26 transformation-specific transcription factor family (5). cancer (2, 3). However, the pathologic consequence of many TMPRSS2–ERG gene fusions juxtapose the androgen-responsive TMPRSS2 gene promoter with the ERG gene coding region. Such 1Department of Urology, the Fourth Hospital of Harbin Medical University, fusions result in aberrant overexpression of ERG in approximately Harbin, Heilongjiang, China. 2Department of Biochemistry and Molecular Biol- 50% of both primary and advanced human prostate cancer, ogy, Mayo Clinic College of Medicine, Rochester, Minnesota. 3Department of suggesting a causal role of ERG in prostate tumorigenesis and Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota. 4Department progression. of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Roche- Since the firstreportoftheTMPRSS2–ERG gene fusion by ster, Minnesota. 5Department of Biochemistry and Molecular Biology, Shenzhen 6 Tomlins and colleagues (4), more than 20 different types of University School of Medicine, Shenzhen, China. Department of Cancer Biology, fi The University of Texas MD Anderson Cancer Center, Houston, Texas. 7Depart- gene rearrangements have been identi ed in prostate cancer ment of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota. 8Mayo patient samples (6, 7). Among these, fusion of TMPRSS2 exon Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota. 1 (a noncoding exon) to ERG exon 4 or 5 (designated as T1/E4 Note: Supplementary data for this article are available at Cancer Research and T1/E5, respectively) are the two most frequently detected Online (http://cancerres.aacrjournals.org/). TMPRSS2–ERG rearrangements in patients (6, 7). Notably, fi Corresponding Authors: Haojie Huang, Mayo Clinic, 200 First Street SW, Gugg mice with prostate-speci c transgenic expression of T1/E4 ERG 1311B, Rochester, MN 55905. Phone: 507-293-1712; Fax: 507-293-3071; E-mail: develop very minor cancer precursor-like lesions, but not [email protected]; and Wanhai Xu, the Fourth Hospital of Harbin Medical prostate neoplasia (8–11), suggesting that ERG requires other University, #37 Yiyuan Street, Nangang District, Harbin, Heilongjiang 150001, lesion(s) to drive prostate tumorigenesis. Indeed, further stud- China. E-mail: [email protected] ies demonstrate that T1/E4 ERG cooperates with Pten deletion doi: 10.1158/0008-5472.CAN-17-0686 or AKT activation to induce prostate cancer in mice (8, 9, 12). Ó2017 American Association for Cancer Research. Conversely, ERG overexpression is also linked with aspects 6524 Cancer Res; 77(23) December 1, 2017 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 6, 2017; DOI: 10.1158/0008-5472.CAN-17-0686 Cooperation of FOXO1 Loss and ERG in Tumorigenesis of later-stage tumors, such as cell invasion. ERG regulates light chain specific rabbit IgG secondary antibody (211-032-171; expression of matrix metalloproteinase genes MMP3, MMP9, Jackson ImmunoResearch Laboratories); ECL anti-rabbit (or anti- ADAM19, plasminogen activator pathway genes PLAT and mouse) IgG horseradish peroxidase–linked whole antibody (GE PLAU, and chemokine receptor CXCR4 in prostate cancer Healthcare UK Limited). Antibodies used for coimmunoprecipi- (11, 13). However, it remains unclear which other prostate tation (co-IP) were: mouse IgG and rabbit IgG (Vector Labora- cancer–relevant lesions may cooperate with ERG overexpres- tories, Inc.); anti-Myc (2276) and anti-FOXO1 (9462L; Cell sion to promote both prostate tumorigenesis and tumor Signaling Technology). Antibodies used for chromatin immuno- progression. precipitation (ChIP) were: rabbit IgG (Vector Laboratories, Inc.); Forkhead box transcription factors FOXO1, FOXO3, FOXO4, anti-ERG (ab92513; Abcam). and FOXO6 (the human orthologs of Caenorhabditis elegans DAF- 16 and Drosophila melanogaster dFOXO) are often recognized as Cell lines, cell culture, and transfection tumor suppressors (14). Activation of these factors results in The cell lines VCaP, PC-3, and LAPC-4 were purchased from transcriptional upregulation of genes involved in apoptosis ATCC and authenticated via STR profiling. VCaP cells were cul- KIP1 CIP1 (e.g., Bim and FasL), cell-cycle arrest (e.g., p27 and p21 ), tured in DMEM (Corning cellgro) supplemented with 13% FBS fi and oxidative stress detoxi cation (e.g., MnSOD and Catalase; (Thermo Fisher Scientific 10437028). PC-3 cells were cultured in – refs. 15 19). Mouse genetic studies demonstrate that somatic RPMI1640 medium (Corning cellgro) supplemented with 10% deletion of Foxo genes promotes formation of a cancer-prone FBS (Thermo Fisher Scientific 10437028). LAPC-4 cells were condition characterized by thymic lymphomas and hemangio- cultured in Iscove's Modified Dulbecco's Medium (Corning cell- fi mas, suggesting that FOXOs are bona de tumor suppressors (20). gro) supplemented with 15% FBS (Thermo Fisher Scientific Moreover, FOXO1 and other FOXO proteins function as key 10437028). Potential contamination mycoplasma was often downstream effectors of the PTEN tumor suppressor (21). Inter- checked using the Lookout Mycoplasma PCR Detection Kit pur- estingly, the PTEN tumor suppressor gene is frequently deleted in chased from Sigma-Aldrich. Cell culture medium was routinely human prostate cancer and occurs concomitantly with ERG over- supplied with Plasmocin (InvivoGen) to prevent mycoplasma expression (9). PTEN loss leads to AKT and CDK1- or CDK2- contamination. Transfections were performed following manu- mediated phosphorylation of FOXO1, exclusion of FOXO1 from facturer's instructions with Lipofectatmine2000 (Thermo Fisher the nucleus, and loss of the tumor suppressor functions in the Scientific) or by electroporation using Electro Square Porator ECM – nucleus (15, 22 24). Increasing evidence suggests that AKT- 830 (BTX) with Mirus Ingenio solution. Approximately 75–90% phosphorylated FOXO1 also possesses tumor suppressor func- transfection efficiencies were achieved. tions in the cytoplasm (25–27). In agreement with these findings, proteosome degradation of AKT-phosphorylated FOXO1 is crit- RNA interference ical for PI3K-AKT-mediated cell transformation and oncogenesis Cells were transfected with siRNA following manufacturer's (28–30). In addition to PTEN defect-caused inactivation of instructions, by electroporation. Nonspecific control siRNA was FOXO1, the FOXO1 gene is also frequently deleted at the genomic purchased from RIBOBIO (siN05815122147). siRNA for PTEN level or downregulated at the transcriptional level in human was purchased from Thermo Fisher Scientific (M00302302), for prostate cancer (31). ERG was purchased from Dharmacon (M003886010005),
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