title: ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.
abstract: Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca(2+)-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial-mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(-) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer.
  
  
  CONCLUSIONS
  ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers.
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Griner
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Denise
authors.initials: D
authors.lastname: Young
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mohamed
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Taduru
authors.initials: T
authors.lastname: Sreenath
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Albert
authors.initials: A
authors.lastname: Dobi
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Jamboor K
authors.initials: JK
authors.lastname: Vishwanatha
authors.affiliation: Joint Pathology Center, Silver Spring, Maryland.
authors.forename: Isabell A
authors.initials: IA
authors.lastname: Sesterhenn
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
authors.forename: Shiv
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland. Stan@cpdr.org.
authors.forename: Shyh-Han
authors.initials: SH
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D017306:Annexin A2 / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D020764:cdc42 GTP-Binding Protein