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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Vydáno v:	Clinical pharmacology and therapeutics Ročník 104; číslo 1; s. 201 - 210
Hlavní autoři:	Qin, Sisi, Liu, Duan, Kohli, Manish, Wang, Liguo, Vedell, Peter T., Hillman, David W., Niu, Nifang, Yu, Jia, Weinshilboum, Richard M., Wang, Liewei
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.07.2018
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	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