title: Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1.
abstract: Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition.
authors.forename: Tae-Dong
authors.initials: TD
authors.lastname: Kim
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.forename: Sook
authors.initials: S
authors.lastname: Shin
authors.forename: Sangphil
authors.initials: S
authors.lastname: Oh
authors.forename: Stan A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; C490641:Etv1 protein, mouse; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D056466:Histone Demethylases; C560307:JMJD2A protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human