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Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1
Tae-Dong Kim, … , Jonathan D. Wren, Ralf Janknecht
Tae-Dong Kim, … , Jonathan D. Wren, Ralf Janknecht
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):706-720. https://doi.org/10.1172/JCI78132.
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Research Article Oncology Article has an altmetric score of 1

Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1

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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

Tae-Dong Kim, Fang Jin, Sook Shin, Sangphil Oh, Stan A. Lightfoot, Joseph P. Grande, Aaron J. Johnson, Jan M. van Deursen, Jonathan D. Wren, Ralf Janknecht

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Figure 1

Interaction of JMJD2A with ETV1.

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Interaction of JMJD2A with ETV1.
(A) Coimmunoprecipitation assays of Fla...
(A) Coimmunoprecipitation assays of Flag2-ETV1 with 16 different 6Myc-tagged JMJD proteins (denoted by asterisks) in 293T cells. (B) Activation of an MMP1 luciferase reporter in BPH-1 cells. Luciferase activities shown are the average of 3 biological replicates with SD evaluated with 1-way ANOVA. (C) JMJD2A coprecipitates with ETV1 in MDA-MB-231 and LNCaP cells. (D) In vitro interaction of purified, Flag-tagged JMJD2A with GST-ETV1 (top). Coomassie-stained gels show the purity and relative amounts of utilized proteins (bottom).

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