The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes.

Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype

UBIAD1 Mutation Alters a Mitochondrial Prenyltransferase to Cause Schnyder Corneal Dystrophy

Abstract Background: Mutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure

UBIAD1 Mutation Alters a Mitochondrial Prenyltransferase to Cause Schnyder Corneal Dystrophy

Peer reviewe

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Penn clinical manual of urology /

Introducing the Penn Clinical Manual of Urology. This one-volume reference presents the key clinical information you need to diagnose and treat urologic disorders quickly and effectively. Brief/, well-illustrated chapters combine an easy-to-read format with the comprehensive coverage you demand. This is a unique offering that deserves a place on every urologist's shelf. Find information quickly and easily with clearly presented algorithms, tables, and figures; an excellent resource for clinical questions and answers. Get the true high-quality information you expect in an easy access, quick reference format. Brush up or prepare for board review using the self-assessment questions at the end of each chapter.Includes bibliographical references and index.Print version record.1. Anatomy of the Urogenital Tract/ John F. Redman -- 2. Laparoscopic Anatomy/ Laparoscopy/ and Robotic-Assisted Laparoscopic Surgery/ David I. Lee -- 3. Signs and Symptoms: The Initial Examination/ Keith Van Arsdalen -- 4. Diagnostic and Interventional Uroradiology/ Parvati Ramchandani -- 5. Urinary Infections in Women/ Philip M. Hanno -- 6. Urinary Infection/Inflammation in Men (Including Retroperitoneal Fibrosis)/ Michael A. Pontari -- 7. Painful Bladder Syndrome/ Philip Hanno -- 8. Urolithiasis/ John J. Pahira -- 9. Emergency Room Urology/ Jeffrey P. Weiss -- 10. Urologic Trauma/ Hunter Wessels -- 11. Urethral Stricture Disease/ Michael J. Metro -- 12. Urinary Fistula/ Eric Rovner -- 13. Voiding Function/ Dysfunction and Urinary Incontinence/ Alan J. Wein & M. Louis Moy -- 14. Benign Prostatic Hyperplasia/ Alan J. Wein -- 15. Prostate and Bladder Cancer/ S. Bruce Malkowicz & David Vaughn -- 16. Renal/ Testicular and Penile Cancer/ Ricardo Sanchez-Ortiz -- 17. Radiation Therapy/ Richard Whittington -- 18. Male Sexual Dysfunction/ Andrew C. Axilrod -- 19. Fertility and Infertility/ Paul Turek -- 20. Sexually Transmitted Disease/ Edward Zoltan -- 21. Disorders of the Adrenal Gland/ Alexander Kutikov -- 22. Renal Transplantation -- 23. Renal Vascular Disease/ Jeffrey Carpenter -- 24. Disorders of Sexual Differentiation/ Thomas F. Kolon -- 25. Pediatric Oncology/ Howard M. Snyder III & Michael C Carr -- 26. Enuresis and Voiding Dysfunction in Children/ Stephen A. Zderic -- 27. Congenital Anomalies/ Pasquale Casale & Douglas A. Canning -- 28. Specific Infections/ Ashok Batra.Introducing the Penn Clinical Manual of Urology. This one-volume reference presents the key clinical information you need to diagnose and treat urologic disorders quickly and effectively. Brief/, well-illustrated chapters combine an easy-to-read format with the comprehensive coverage you demand. This is a unique offering that deserves a place on every urologist's shelf. Find information quickly and easily with clearly presented algorithms, tables, and figures; an excellent resource for clinical questions and answers. Get the true high-quality information you expect in an easy access, quick reference format. Brush up or prepare for board review using the self-assessment questions at the end of each chapter.Elsevie