Therapeutic Targeting of Histone Lysine Demethylase KDM4B Blocks the Growth of Castration-resistant Prostate Cancer
Year: 2021
Type: preprint
Abstract: Background: Accumulating evidence points to epigenetic mechanisms as essential in tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated a correlation of levels of histone lysine demethylase KDM4B with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we aim to define the role of KDM4B in promoting PCa progression and test the efficacy of B3 using clinically relevant PCa models. Methods: KDM4B was overexpressed in LNCaP cells or knocked down (KD) in 22Rv1 cells. The specificity of B3 was determined in vitro using recombinant KDM proteins and in vivo using 22Rv1 cell lysates. The efficacy of B3 monotherapy or in combination with androgen receptor (AR) antagonist enzalutamide or the mTOR inhibitor rapamycin was tested using xenograft models in castrated mice. Comparative transcriptomic analysis was performed on KDM4B KD and B3-treated 22Rv1 cells to determine the on-target (KDM4B-dependent) and off-target (non-KDM4B-associated) effects of B3.Results: Overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of both 22Rv1 and VCaP xenografts and sensitized 22Rv1 cells to enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin that resulted in cell apoptosis. Mechanistically, B3 inhibited expression of AR-V7 and genes involved in epithelial-to-mesenchymal transition. DNA replication stress marker γH2A.X was upregulated by B3, which is further increased when combined with rapamycin. Based on transcriptomic and biochemical analyses, B3 inhibits both H3K9me3 and H3K27me3 demethylase activity, which is believed to underlie its anti-tumor action.Conclusions: Our studies establish KDM4B as a potent target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMSs for CRPC patients.
Source: Research Square
Authors: Lingling Duan, Yu-An Chen, Yanping Liang, Zhenhua Chen, Jun Lu, Yong Fang, Jiazheng Cao, Jian Lu, Hongwei Zhao, Rey-Chen Pong, Elizabeth Hernandez, Payal Kapur, Tram Anh T Tran, Tristan Smith, Elisabeth D. Martinez, Jung-mo Ahn, Jer-Tsong Hsieh, Junhang Luo, Zhi-Ping Liu
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: P4: Rational design of peptidomimetics that target the lysine demethylases and their binding to the androgen receptor in prostate cancer, G1615321815, G2155110812, G3052324272, G3119154196, Bioinformatics Core Facility at UT Southwestern Medical Center, G426852193, G5364085176, P1: Targeting epigenetic co-activators of AR with small molecule inhibitors, G6526792485, G7105029878, G7384085626, Administrative Core, G7765267405, G7806958584, G8617707730, G8698817331, G9000043488, G9000347283, G963705879
OpenAlex ID: W4243363494