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Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression

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Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression Published OnlineFirst September 18, 2018; DOI: 10.1158/1078-0432.CCR-18-2392 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression Xiaomei Gao1,2, Charles Dai3, Shengsong Huang4, Jingjie Tang1,2, Guoyuan Chen1, Jianneng Li3, Ziqi Zhu3, Xuyou Zhu5, Shuirong Zhou1,2, Yuanyuan Gao1,2, Zemin Hou1,2, Zijun Fang1,2, Chengdang Xu4, Jianyang Wang1,2, Denglong Wu4, Nima Sharifi3,6,7, and Zhenfei Li1,2 Abstract Purpose: Steroidogenic enzymes are essential for prostate (DHT) to each of their upstream precursors. HSD17B2 over- cancer development. Enzymes inactivating potent androgens expression suppressed androgen-induced cell proliferation were not investigated thoroughly, which leads to limited inter- and xenograft growth. Multiple mechanisms were involved ference strategies for prostate cancer therapy. Here we charac- in HSD17B2 functional silencing including DNA methylation terizedtheclinical relevance,significance, andregulation mech- and mRNA alternative splicing. DNA methylation decreased anism of enzyme HSD17B2 in prostate cancer development. the HSD17B2 mRNA level. Two new catalytic-deficient iso- Experimental Design: HSD17B2 expression was detected forms, generated by alternative splicing, bound to wild-type with patient specimens and prostate cancer cell lines. Function 17bHSD2 and promoted its degradation. Splicing factors of HSD17B2 in steroidogenesis, androgen receptor (AR) sig- SRSF1 and SRSF5 participated in the generation of new naling, and tumor growth was investigated with prostate isoforms. cancer cell lines and a xenograft model. DNA methylation Conclusions: Our findings provide evidence of the clinical and mRNA alternative splicing were investigated to unveil the relevance, significance, and regulation of HSD17B2 in prostate mechanisms of HSD17B2 regulation. cancer progression, which might provide new strategies for Results: HSD17B2 expression was reduced as prostate can- clinical management by targeting the functional silencing cer progressed. 17bHSD2 decreased potent androgen produc- mechanisms of HSD17B2. tion by converting testosterone (T) or dihydrotestosterone See related commentary by Mostaghel, p. 1139 Introduction mote prostate cancer progression (3). Thus, steroidogenic enzymes involved in androgen metabolism are essential targets Prostate cancer is the most common cancer in the United for prostate cancer treatment or biomarkers for disease diag- States and the fastest increasing cancer in China in men (1, 2). nosis (4, 5). Androgens activate androgen receptor (AR) signaling to pro- Testosterone (T) produced by testis is the major androgen- stimulating prostate cancer development until androgen dep- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular rivation therapy (ADT; ref. 6). ADT resistance occurs and Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese disease progresses into castration-resistant prostate cancer Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, (CRPC) by utilizing adrenal precursors, such as DHEA P.R. China. 2CAS Key Laboratory of Systems Biology, CAS Center for Excellence or androstenedione (AD), to generate potent androgen in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, DHT (3, 7, 8). Steroidogenic enzymes that accelerate DHT Chinese Academy of Sciences, Shanghai, P.R. China. 3Department of Cancer synthesis have been investigated thoroughly in driving prostate Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. 4Depart- ment of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, cancer development and treatment resistance (9, 10). CYP17A P.R. China. 5Department of Pathology, Tongji Hospital, Tongji University School is required for conversion of cholesterol to DHEA, providing of Medicine, Shanghai, P.R. China. 6Department of Urology, Glickman Urological androgen precursors to prostate cancer (7). Abiraterone, target- and Kidney Institute, Cleveland Clinic, Cleveland, Ohio. 7Department of Hema- ing CYP17A, is used for treatment of CRPC and castration- tology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. sensitive prostate cancer (11–14). 3bHSD1 is the rate-limiting Note: Supplementary data for this article are available at Clinical Cancer enzyme for DHEA to DHT metabolism. A SNP in 3bHSD1 Research Online (http://clincancerres.aacrjournals.org/). increases its protein stability and leads to worse outcomes after X. Gao, C. Dai, S. Huang, and J. Tang contributed equally to this article. ADT (15–19). Increased expression of AKR1C3 has been Corresponding Authors: Zhenfei Li, State Key Laboratory of Cell Biology, CAS reported as a mechanism of drug resistance. AKR1C3 catalyzes Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochem- AD or 5a-androstanedione (5a-dione) to T or DHT, respec- istry and Cell Biology, Chinese Academy of Sciences; University of Chinese tively, by modifying the 17-keto group to 17b-OH which is Academy of Sciences, Shanghai 200031, P.R. China. Phone: 86-21-54921339; essential for AR activation (20, 21). Increasing AKR1C3 leads E-mail: [email protected]; Nima Sharifi, [email protected]; and Denglong Wu, to more efficient steroidogensis, which could subdue the [email protected] response to abiraterone or enzalutamide (22, 23). Thus, ste- doi: 10.1158/1078-0432.CCR-18-2392 roidogenic enzymes promoting androgen synthesis obtain Ó2018 American Association for Cancer Research. oncogenic function in disease development. www.aacrjournals.org 1291 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 18, 2018; DOI: 10.1158/1078-0432.CCR-18-2392 Gao et al. 50-TCAAGCCCCAAAAAGGGGAC-30 and gD: 50-TGTCCATTTG- Translational Relevance 0 GAGCACCGAG-3 ) were inserted into CRISPR plasmid back- Androgens sustain prostate cancer development. Steroido- bone, lentiCRISPR v2 [a generous gift from Dr. Feng Zhang genic enzymes promoting androgen synthesis are well- (Addgene Plasmid #52961)] according to the protocol they established therapeutic targets and predictive biomarkers, provided (28). Then they were used to generate the HSD17B2 while enzymes inactivating androgens have not been investi- knockout MDA-PCa-2b stable cell line by using a lentiviral gated thoroughly. Here we show the clinical relevance and system. 293T cells were cotransfected with 10 mg each of con- significance of HSD17B2 in prostate cancer, providing poten- structed plasmids (containing gRNAs), pMD2.G, and psPAX2 tial biomarker for disease diagnosis. Mechanisms of HSD17B2 vector for 48 hours to package the virus. Then the virus was functional silencing were further investigated to provide concentrated by using PEG-it Virus Precipitation Solution (Sys- potential novel strategies for disease intervention. tem Biosciences) according to the provided protocol. Next, MDA- PCa-2b cells were infected with the concentrated virus for 24 hours with addition of polybrene (10 mg/mL), followed by selection with 2 mg/mL puromycin for nearly 2 weeks. However, steroidogenic enzymes that inactivate androgens have not been investigated thoroughly. The regulation of andro- High-performance liquid chromatography gen-inactivation enzymes is not well understood as is their role in Cells were seeded and incubated in 24-well plates with 0.2 b million cells/well for nearly 24 hours and then treated with tumor progression. The enzyme 17 HSD2 catalyzes the reverse 3 reaction of AKR1C3. It catalyzes 17b-OH to 17-keto and leads to indicated drugs and a mixture of radioactive ([ H]-labeled) and – fi nonradioactive steroids (final concentration, 50 nmol/L T and 10 androgen inactivation (24 27). The signi cance and regulation of 17bHSD2 in prostate cancer remains elusive. nmol/L DHT; nearly 1,000,000 cpm/well; PerkinElmer) at 37 C. Here we show HSD17B2 expression and function is reduced in Aliquots of medium were collected at the indicated time and b prostate cancer. Overexpression of HSD17B2 blocks potent treated with 300 units of -glucuronidase (Novoprotein Scien- fi m androgen synthesis and thus suppresses AR signaling and cell ti cInc.)at37C for 2 hours, extracted with 500 Lethyl growth. In vivo,17bHSD2 inhibits xenograft proliferation as a acetate:isooctane (1:1), dried under freeze dryer (Martin Christ tumor suppressor. The expression of HSD17B2 in prostate cancer Gefriertrocknungsanlagen). is regulated by DNA methylation, androgen stimulation and HPLC analysis was performed on a Waters Acquity ARC m mRNA alternative splicing. Our data demonstrate the tumor HPLC. Dried samples were reconstituted in 100 Lof50% suppressor role of 17bHSD2 and its regulation mechanisms in methanol and injected into the HPLC. Metabolites were sep- Â prostate cancer, shedding light on disease interruption through arated on CORTECS C18 reverse-phase column 4.6 50 mm, m HSD17B2. 2.7 mol/L(Waters)usingamethanol/watergradientat40C. The column effluent was analyzed using b-RAM model 3 in-line Materials and Methods radioactivity detector (LABLOGIC). All HPLC studies were run in triplicate and repeated at least three times in independent Cell lines experiments. Cell lines LNCaP, PC3, Du145, and HEK293T cells were pur- chased from the ATCC and maintained in RPMI1640 (LNCaP, Gene expression and immunoblotting PC3, and Du145) or DMEM (HEK293T) with 10% FBS. Dr. Cells were starved
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