Abstract
Lysine demethylase 5A (KDM5A) is a histone demethylase frequently involved in cancer progression. This research aimed to explore the function of KDM5A in prostate adenocarcinoma (PRAD) and the molecular mechanism. KDM5A was highly expressed in collected PRAD tissues and acquired PRAD cells. High KDM5A expression was correlated with reduced survival and poor prognosis of patients with PRAD. Knockdown of KDM5A suppressed the proliferation, colony formation, migration, and invasiveness of PRAD cells and reduced angiogenesis ability of endothelial cells. Downstream molecules implicated in KDM5A mediation were predicted using integrated bioinformatic analyses. KDM5A enhanced ETS proto-oncogene 1 (ETS1) expression through demethylation of H3K4me2 at its promoter. ETS1 suppressed the transcription activity of miR-330-3p, and either further ETS1 overexpression or miR-330-3p inhibition blocked the functions of KDM5A knockdown in PRAD. miR-330-3p targeted coatomer protein complex subunit β2 (COPB2) mRNA. Downregulation of miR-330-3p restored the expression of COPB2 and activated the PI3K/AKT pathway in PRAD. The results in vitro were reproduced in vivo where KDM5A downregulation suppressed the growth and metastasis of xenograft tumors in nude mice. In conclusion, this study demonstrated that KDM5A promoted PRAD by suppressing miR-330-3p and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner.
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Acknowledgements
This work was supported by National Natural Science Foundation (No. 81802576, 81902565, 81372316), Wuxi City Medical Young Talent (No. QNRC043), Wuxi Commission of Health and Family Planning (No. T202102, T202024, J202012, Z202011, CXTDPY2021003), the Science and Technology Development Fund of Wuxi (No. WX18IIAN024, N20202021), Jiangnan University Wuxi School of Medicine (No. 1286010242190070), Wuxi “Taihu Talent Program”-High-end Talent in Medical and Healthentalent plan of Taihu Lake in Wuxi (Double Hundred Medical Youth Professionals Program) from Health Committee of Wuxi (No. BJ2020061), clinical trial of Affiliated Hospital of Jiangnan University (No. LCYJ202227). The authors are thankful for the guidance of Professor Yongquan Chen.
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YYM, LFZ, CYS and YYF conceived the design of the research and carried out most of the experiments. JS, JW, DJY, XWQ, HYW, SW, GWX and LJZ obtained, analyzed and interpreted the data. YYM, LFZ, CYS and YYF wrote and revised the manuscript. SW and GWX prepared the fgures and provides financial support for all experiments. All authors read and approved the fnal manuscript. We confirmed that no third parties were used in either the writing of the paper or the generation of data.
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Mi, Y., Zhang, L., Sun, C. et al. Lysine demethylase 5A promotes prostate adenocarcinoma progression by suppressing microRNA-330-3p expression and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner. J. Cell Commun. Signal. 16, 579–599 (2022). https://doi.org/10.1007/s12079-022-00671-5
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DOI: https://doi.org/10.1007/s12079-022-00671-5