Functional Silencing of <i>HSD17B2</i> in Prostate Cancer Promotes Disease Progression

Gao, Xiaomei; Dai, Charles; Huang, Shengsong; Tang, Jinshan; Chen, Guoyuan; Li, Jianneng; Zhu, Ziqi; Zhu, Xuyou; Zhou, Shuirong; Gao, Yuanyuan; Hou, Zhufeng; Fang, Zijun; Xu, Chengdang; Wang, Jianyang; Wu, Denglong; Sharifi, Nima; Li, Zhenfei

doi:10.1158/1078-0432.ccr-18-2392

Cited by 44 publications

(31 citation statements)

References 43 publications

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“…Although mCRPC is more likely to occur following ADT, the majority of prostatic adenocarcinomas remain reliant on ARS. Such mechanisms comprise: (1) steroidogenesis upregulation within the prostate tumor, allowing the synthesis of endogenous androgens [ 20 , 73 , 74 ]; (2) higher AR expression in prostate tumor cells, mainly due to AR gene amplification [ 22 ]; (3) single point mutations within AR gene LBD [ 75 , 76 , 77 ]; (4) silencing through methylation of the gene encoding the androgen-inactivation enzyme HSD17B2 [ 78 ]; (5) variants of the HSD3B1 gene [ 79 ]; (6) upregulation of the glucocorticoid receptor [ 80 ], and (7) emergence of AR splice variants.…”

Section: From Alterations To Ar Axis-targeted Therapy Resistancementioning

confidence: 99%

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

Sobhani

Neeli

D’Angelo

et al. 2021

IJMS

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Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.

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Section: From Alterations To Ar Axis-targeted Therapy Resistancementioning

confidence: 99%

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

Sobhani

Neeli

D’Angelo

et al. 2021

IJMS

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“…AKR1C3 , type 5 17β-hydroxysteroid dehydrogenase; HSD11B2, type 2 11β-hydroxysteroid dehydrogenase; and SRD5A1/2 , type 1 and type 2 steroid 5α-reductase (3a-hydroxysteroid oxidase) work as the molecular switch that determines DHT ligand access to the AR in the normal and diseased prostate [53] . HSD17B2 and HSD17B4 by working as 17β-hydroxysteroid oxidases convert T and DHT to their inactive counterparts, e.g., Δ 4 -AD and 5α-androstane-3,17-dione, respectively, and are implicated in the inactivation of these hormones [54,55] . The 5α-androstanediols once formed by AKR1C1 and AKR1C2, can then be glucuronidated by UGT family members UGT2B15 and UGT2B17 [56,57] .…”

Section: Intracrine Androgen Biosynthesismentioning

confidence: 99%

Intracrine androgen biosynthesis and drug resistance

Penning¹,

Asangani²,

Sprenger³

et al. 2020

CDR

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Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.

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“…More so, ~54.3% of patients with metastatic AR positive tumors concurrently expressed enzymes for adrenal androgen utilization, such as SRD5A1 and SHBG, and 25.7% expressed enzymes for de novo steroidogenesis, including hydroxysteroid 17-β-dehydrogenase 2 and 3 (HSD17B2/3) [ 8 ]. It has been suggested that HSD17B2 suppresses androgen production by reverse conversion of testosterone or DHT to their upstream precursors, that the expression of HSD17B2 reduces as PCa progresses, and that the overexpression of HSD17B2 suppresses androgen-induced cell proliferation and xenograft growth [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

Bamodu

Tzou

Lin

et al. 2021

Cancers

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Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

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Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression

Abstract: Our findings provide evidence of the clinical relevance, significance and regulation of HSD17B2 in prostate cancer progression, which might provide new strategies for clinical management by targeting the functional silencing mechanisms of HSD17B2.

Cited by 44 publications

References 43 publications

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

Intracrine androgen biosynthesis and drug resistance

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

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