KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis.

Autor:	Li G; Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee., Kanagasabai T; Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee., Lu W; Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee., Zou MR; Department of Pathology, Yale University, New Haven, Connecticut., Zhang SM; Department of Pathology, Yale University, New Haven, Connecticut., Celada SI; Department of Biological Sciences, Tennessee State University, Nashville, Tennessee., Izban MG; Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, Nashville, Tennessee., Liu Q; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee., Lu T; School of Graduate Studies and Research, Meharry Medical College, Nashville, Tennessee., Ballard BR; Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, Nashville, Tennessee., Zhou X; Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi., Adunyah SE; Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee., Matusik RJ; Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee., Yan Q; Department of Pathology, Yale University, New Haven, Connecticut. zchen@mmc.edu qin.yan@yale.edu., Chen Z; Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee. zchen@mmc.edu qin.yan@yale.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Nov 01; Vol. 80 (21), pp. 4633-4643. Date of Electronic Publication: 2020 Aug 31.
DOI:	10.1158/0008-5472.CAN-20-0505
Abstrakt:	KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b . Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten -null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo . KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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