TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer

Sisi Qin; Duan Liu; Manish Kohli; Liguo Wang; Peter T Vedell; David W Hillman; Nifang Niu; Jia Yu; Richard M Weinshilboum; Liewei Wang

doi:10.1002/cpt.907

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TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer

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TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer

Sisi Qin, Duan Liu, Manish Kohli, Liguo Wang, Peter T Vedell, David W Hillman, Nifang Niu, Jia Yu, Richard M Weinshilboum and Liewei Wang

Clinical pharmacology and therapeutics, Vol.104(1), pp.201-210

07/2018

DOI: 10.1002/cpt.907

PMCID: PMC5899062

PMID: 29027195

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https://doi.org/10.1002/cpt.907View

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Abstract

The testis-specific Y-encoded-like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration-resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression-free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes.

Abiraterone Acetate - pharmacology

Abiraterone Acetate - therapeutic use

Cell Cycle Proteins - drug effects

Cell Cycle Proteins - genetics

Cell Proliferation - drug effects

Cell Proliferation - genetics

Cytochrome P-450 CYP3A - drug effects

Cytochrome P-450 CYP3A - genetics

Cytochrome P-450 CYP3A - metabolism

Cytochrome P-450 Enzyme Inhibitors - pharmacology

Cytochrome P-450 Enzyme Inhibitors - therapeutic use

Dehydroepiandrosterone - metabolism

Gene Expression Regulation - drug effects

Gene Knockdown Techniques

Hep G2 Cells

Humans

Male

Neoplasm Metastasis

Nuclear Proteins - drug effects

Nuclear Proteins - genetics

Proportional Hazards Models

Prostatic Neoplasms, Castration-Resistant - drug therapy

Prostatic Neoplasms, Castration-Resistant - pathology

RNA, Messenger - metabolism

Steroid 17-alpha-Hydroxylase - antagonists & inhibitors

Steroid 17-alpha-Hydroxylase - drug effects

Steroid 17-alpha-Hydroxylase - genetics

Treatment Outcome

Details

Title: Subtitle: TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer
Creators: Sisi Qin - Mayo Clinic
Duan Liu - Mayo Clinic
Manish Kohli - Mayo Clinic
Liguo Wang - Mayo Clinic in Florida
Peter T Vedell - Mayo Clinic in Florida
David W Hillman - Mayo Clinic in Florida
Nifang Niu - Mayo Clinic
Jia Yu - Mayo Clinic
Richard M Weinshilboum - Mayo Clinic
Liewei Wang - Mayo Clinic
Resource Type: Journal article
Publication Details: Clinical pharmacology and therapeutics, Vol.104(1), pp.201-210
DOI: 10.1002/cpt.907
PMID: 29027195
PMCID: PMC5899062
ISSN: 0009-9236
eISSN: 1532-6535
Grant note: R01 GM125633 / NIGMS NIH HHS U19 GM061388 / NIGMS NIH HHS R01 CA196648 / NCI NIH HHS R01 GM028157 / NIGMS NIH HHS
Language: English
Date published: 07/2018
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9984701643002771

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