TY - JOUR
T1 - TSPYL Family Regulates CYP17A1 and CYP3A4 Expression
T2 - Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer
AU - Qin, Sisi
AU - Liu, Duan
AU - Kohli, Manish
AU - Wang, Liguo
AU - Vedell, Peter T.
AU - Hillman, David W.
AU - Niu, Nifang
AU - Yu, Jia
AU - Weinshilboum, Richard M.
AU - Wang, Liewei
N1 - Funding Information:
This work was supported by National Institutes of Health grants U19 GM61388 (The Pharmacogenomics Research Network), R01 CA196648, R01 GM28157, Minnesota Partnership for Biotechnology and Medical Genomics Grant #14.37, Department of Defense, Prostate Cancer Foundation, and Private and philanthropy funding sources: i) Mayo Clinic Center for Individualized Medicine; ii) A.T. Suharya and Ghan D.H, Gail and Joseph Gassner; iii) Mayo Clinic Schulze Cancer for Novel Therapeutics in Cancer Research.
Funding Information:
This work was supported by National Institutes of Health grants U19 GM61388 (The Pharmacogenomics Research Network), R01 CA196648, R01 GM28157, Minnesota Partnership for Biotechnology and Medical Genomics Grant #14.37, Department of Defense, Prostate Cancer Foundation, and Private and philanthropy funding sources: i) Mayo Clinic Center for Individualized Medicine; ii) A.T. Suharya and Ghan D.H, Gail and Joseph Gassner; iii) Mayo Clinic Schulze Cancer for Novel Therapeutics in Cancer Research. The AA/P clinical study (https://clinicaltrials.gov/ identifier NCT # 01953640) was reviewed and approved by the Mayo Clinic Institution Review Board (IRB), with written informed consent provided by all enrolled patients. S.Q., D.L., and L.W.W. wrote the article; L.W.W., R.W., S.Q., D.L., and M.K. designed the research; S.Q., D.L., N.N., and J.Y. performed the research; L.W.G., P.V., and D.H. analyzed the data. The first two authors contributed equally to this work.
Publisher Copyright:
© 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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.
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U2 - 10.1002/cpt.907
DO - 10.1002/cpt.907
M3 - Article
C2 - 29027195
AN - SCOPUS:85034735446
SN - 0009-9236
VL - 104
SP - 201
EP - 210
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 1
ER -