Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer

Ko, Hyun Kyung; Berk, Michael; Chung, Yoon Mi; Willard, Belinda; Bareja, Rohan; Rubin, Mark A.; Sboner, Andrea; Sharifi, Nima

doi:10.1016/j.celrep.2017.12.081

Cited by 31 publications

(26 citation statements)

References 46 publications

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“…The present study is the first to assess the functional validation of PGRMC1 and HSD17B4 in human PCa. Consistent with previous findings, we report that HSD17B4 is highly expressed in PCa cell lines DU145 and PC3 . However, we are the first to illustrate expression of PGRMC1 in PCa cells.…”

Section: Discussionsupporting

confidence: 92%

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

et al. 2019

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Background: Gleason grade is among the most powerful clinicopathological classification systems used to assess risk of lethal potential in prostate cancer, yet its biologic basis is poorly understood. Notably, pure low-grade cancers, comprised predominantly of Gleason pattern 3 (G3) are typically indolent, with lethal potential emerging with the progression of higher-grade Gleason patterns 4 (G4) or 5. One of the hallmarks of more aggressive cancer phenotypes is the stereotyped set of metabolic characteristics that transformed cells acquire to facilitate unregulated growth. In the present study, we profiled expression signatures of metabolic genes that are differentially expressed between G3 and G4 cancer foci and investigated the functional role of two of the profiled genes, PGRMC1 and HSD17B4, in prostate cancer cells.Methods: Gene expression profiling was conducted using 32 G3 and 32 G4 cancer foci from patients with 3+3 and ≥4+3 tumors, respectively. A 95-gene Nanostring probe set was used to probe genes associated with energy metabolism. Two out of five genes (PGRMC1 and HSD17B4) that significantly distinguish between G3 and G4 were functionally validated in vitro using established prostate cancer cells (PC3, DU145). Expression of PGRMC1 and HSD17B4 was knocked down and subsequent studies were performed to analyze cell proliferation, migration, invasion, and apoptosis. Mechanistic studies that explored the epidermal growth factor receptor (EGFR) pathway were performed by Western blot.Results: Multivariate analysis identified five metabolic genes that were differentially expressed between G3 and G4 stroma (P < .05). Functional validation studies revealed that knockdown of PGRMC1 and HSD17B4 significantly decreased cell proliferation, migration, and invasion, and increased apoptosis in PC3 and DU145 cells. Mechanistic studies showed that these effects, after PGRMC1 knockdown, were possibly mediated through alterations in downstream components of the EGFR, protein kinase B, and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. Conclusion:The following study provides evidence supporting the use of metabolic genes PGRMC1 and HSD17B4 as a prognostic biomarker for the distinction between G3 and G4 prostate cancers. K E Y W O R D Sbiomarkers, functional validation, Gleason score, metabolism, prostate cancer

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Section: Discussionsupporting

confidence: 92%

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

et al. 2019

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“…This is in line with reports that indicate adrenal androgens are the principle source of intratumoral androgens in CRPC (13,14). Furthermore, the more rapid production of androgens during ADT due to genomic variants has also been shown to correspond to poorer prognosis (15)(16)(17). The reasons for these changes over time cannot be determined from our data, but similar changes in patient sera have been reported following enzalutamide treatment (18).…”

Section: Discussionsupporting

confidence: 92%

Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial

Toren

Hoffman

Ding

et al. 2018

Clinical Cancer Research

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Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry. Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E) and estradiol (E) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups. Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E and E and rising DHEA and AST levels, which predict a shorter time to CRPC. .

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“…In fact, dy-regulations of peroxisomal enzymes and/or their effects were shown in numerous tumor types including prostate cancer (Ko et al, 2018), colorectal carcinoma (Lakis et al, 2010), liver cancer (Lu et al, 2015;Chen et al, 2018), oral squamous cell carcinoma (Lai et al, 2018), pancreatic cancer (Deplanque et al, 2015), breast cancer (Keller et al, 1993), and lymphoma (Zheng et al, 2019). However, there was no systemic study of peroxisomes in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

et al. 2020

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To explore the potential functions and clinical significances of peroxisomes during lung cancer development and progression, we investigated the expressional profiles of peroxisome pathway genes and their correlations with clinical features in nonsmall cell lung cancer (NSCLC). The RNA-seq data of NSCLC including lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with their clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene expression comparisons between tumor and normal samples were performed with edgeR package in R software and the results of the 83 peroxisome pathway genes were extracted. Through Venn diagram analysis, 38 common differentially expressed peroxisome pathway genes (C-DEPGs) in NSCLC were identified. Principal components analysis (PCA) was performed and the 38 C-DEPGs could discriminate NSCLC tumors from the non-tumor controls well. Through Kaplan-Meier survival and Cox regression analyses, 11 of the C-DEPGs were shown to have prognostic effects on NSCLC overall survival (OS) and were considered as key C-DEPGs (K-DEPGs). Through Oncomine, Human Protein Atlas (HPA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), three K-DEPGs (HSD17B4, ACAA1, and PXMP4) were confirmed to be down-regulated in NSCLC at both mRNA and protein level. Their dyregulation mechanisms were revealed through their correlations with their copy number variations and methylation status. Their potential functions in NSCLC were explored through their NSCLC-specific co-expression network analysis, their correlations with immune infiltrations, immunomodulator gene expressions, MKI67 expression and their associations with anti-cancer drug sensitivity. Our findings suggested that HSD17B4, ACAA1, and PXMP4 might be new markers for NSCLC diagnosis and prognosis and might provide new clues for NSCLC treatment.

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Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer

Cited by 31 publications

References 46 publications

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

Functional validation of metabolic genes that distinguish Gleason 3 from Gleason 4 prostate cancer foci

Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

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