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

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 ke...

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Veröffentlicht in:Clinical pharmacology and therapeutics Jg. 104; H. 1; S. 201 - 210
Hauptverfasser: Qin, Sisi, Liu, Duan, Kohli, Manish, Wang, Liguo, Vedell, Peter T., Hillman, David W., Niu, Nifang, Yu, Jia, Weinshilboum, Richard M., Wang, Liewei
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.07.2018
Schlagworte:
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
ISSN:0009-9236, 1532-6535, 1532-6535
Online-Zugang:Volltext
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0009-9236
1532-6535
1532-6535
DOI:10.1002/cpt.907