Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer
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(Published version)
Date
2022
Authors
Yoshikawa, Y.
Stopsack, K.H.
Wang, X.V.
Chen, Y.H.
Mazzu, Y.Z.
Burton, F.
Chakraborty, G.
Rajanala, S.H.
Hirani, R.
Nandakumar, S.
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Journal article
Citation
Molecular Oncology, 2022; 16(22):3994-4010
Statement of Responsibility
Yuki Yoshikawa, Konrad H. Stopsack, Xin Victoria Wang, Yu-Hui Chen, Ying Z. Mazzu, Foster Burton, Goutam Chakraborty, Sai Harisha Rajanala, Rahim Hirani, Subhiksha Nandakumar, Gwo-Shu Mary Lee, David Frank, Elai Davicioni, Glenn Liu, Michael A. Carducci, Haruhito Azuma, Philip W. Kantoff, and Christopher J. Sweeney
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Abstract
Loss of the histone demethylase KDM5D (lysine-specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP-seq) of the LNCaP cell line (androgen-sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2-binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone-sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)-positive hormone-sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line-specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone-sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone-sensitive prostate cancer.
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© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.