BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence

Lei Gu; Sandra C Frommel; Christopher C Oakes; Ronald Simon; Katharina Grupp; Cristina Y Gerig; Dominik Bär; Mark D Robinson; Constance Baer; Melanie Weiss; Zuguang Gu; Matthieu Schapira; Ruprecht Kuner; Holger Sültmann; Maurizio Provenzano; ICGC Project on Early Onset Prostate Cancer; Marie-Laure Yaspo; Benedikt Brors; Jan Korbel; Thorsten Schlomm; Guido Sauter; Roland Eils; Christoph Plass; Raffaella Santoro

doi:10.1038/ng.3165

BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence

Nat Genet. 2015 Jan;47(1):22-30. doi: 10.1038/ng.3165. Epub 2014 Dec 8.

Authors

Lei Gu¹, Sandra C Frommel², Christopher C Oakes³, Ronald Simon⁴, Katharina Grupp⁴, Cristina Y Gerig⁵, Dominik Bär⁵, Mark D Robinson⁶, Constance Baer³, Melanie Weiss³, Zuguang Gu⁷, Matthieu Schapira⁸, Ruprecht Kuner⁹, Holger Sültmann⁹, Maurizio Provenzano¹⁰; ICGC Project on Early Onset Prostate Cancer; Marie-Laure Yaspo¹¹, Benedikt Brors⁷, Jan Korbel¹², Thorsten Schlomm¹³, Guido Sauter⁴, Roland Eils¹⁴, Christoph Plass³, Raffaella Santoro⁵

Affiliations

¹ 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² 1] Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland. [2] Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland.
³ Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
⁶ 1] Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. [2] Swiss Institute of Bioinformatics (SIB), University of Zurich, Zurich, Switzerland.
⁷ Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
⁹ Unit of Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center of Tumour Diseases, Heidelberg, Germany.
¹⁰ Oncology Research Unit, Division of Urology, University Hospital of Zurich, Zurich, Switzerland.
¹¹ Max Planck Institute for Molecular Genetics, Berlin, Germany.
¹² Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
¹³ Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.

PMID: 25485837
DOI: 10.1038/ng.3165

Abstract

Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic alterations are frequently observed in all human cancers, yet how aberrant epigenetic signatures are established is poorly understood. Here we show that the gene encoding BAZ2A (TIP5), a factor previously implicated in epigenetic rRNA gene silencing, is overexpressed in prostate cancer and is paradoxically involved in maintaining prostate cancer cell growth, a feature specific to cancer cells. BAZ2A regulates numerous protein-coding genes and directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis. BAZ2A overexpression is tightly associated with a molecular subtype displaying a CpG island methylator phenotype (CIMP). Finally, high BAZ2A levels serve as an independent predictor of biochemical recurrence in a cohort of 7,682 individuals with prostate cancer. This work identifies a new aberrant role for the epigenetic regulator BAZ2A, which can also serve as a useful marker for metastatic potential in prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Biomarkers, Tumor / genetics
Cell Division
Cell Line, Tumor
Chromosomal Proteins, Non-Histone / biosynthesis
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / physiology*
CpG Islands
DNA Methylation
Enhancer of Zeste Homolog 2 Protein
Epigenetic Repression*
Follow-Up Studies
Gene Expression Regulation, Neoplastic*
Humans
Male
Neoplasm Invasiveness / genetics
Neoplasm Metastasis / genetics*
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Polycomb Repressive Complex 2 / physiology
Prognosis
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Protein Interaction Mapping
RNA, Neoplasm / biosynthesis
RNA, Ribosomal / biosynthesis
Up-Regulation

Substances

BAZ2A protein, human
Biomarkers, Tumor
Chromosomal Proteins, Non-Histone
Neoplasm Proteins
RNA, Neoplasm
RNA, Ribosomal
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2

Grants and funding

092809/Wellcome Trust/United Kingdom