Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.

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 in 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 on 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.

Molecular oncology. 2022 Sep 10 [Epub ahead of print]

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, Christopher J Sweeney

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY., Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Decipher Biosciences Inc., San Diego, CA., University of Wisconsin Carbone Cancer Center, Madison, WI., Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD., Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.