ESS2 controls prostate cancer progression through recruitment of chromodomain helicase DNA binding protein 1

Sayuri Takahashi; Ichiro Takada; Kenichi Hashimoto; Atsushi Yokoyama; Tohru Nakagawa; Makoto Makishima; Haruki Kume

doi:10.1038/s41598-023-39626-0

ESS2 controls prostate cancer progression through recruitment of chromodomain helicase DNA binding protein 1

Sci Rep. 2023 Jul 31;13(1):12355. doi: 10.1038/s41598-023-39626-0.

Authors

Sayuri Takahashi^{1

2}, Ichiro Takada^{3

4}, Kenichi Hashimoto⁵, Atsushi Yokoyama⁶, Tohru Nakagawa⁷, Makoto Makishima⁴, Haruki Kume^{3

5}

Affiliations

¹ Department of Urology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan. t-sayuri@athena.ocn.ne.jp.
² Department of Urology, The Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan. t-sayuri@athena.ocn.ne.jp.
³ Department of Urology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan.
⁴ Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University, Itabashi-Ku, Tokyo, 173-8610, Japan.
⁵ Department of Urology, The Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
⁶ Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
⁷ Department of Urology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan.

Abstract

Molecular targeted therapy using poly (ADP-ribose) polymerase inhibitors has improved survival in patients with castration-resistant prostate cancer (CRPC). However, this approach is only effective in patients with specific genetic mutations, and additional drug discovery targeting epigenetic modulators is required. Here, we evaluated the involvement of the transcriptional coregulator ESS2 in prostate cancer. ESS2-knockdown PC3 cells dramatically inhibited proliferation in tumor xenografts in nude mice. Microarray analysis revealed that ESS2 regulated mRNA levels of chromodomain helicase DNA binding protein 1 (CHD1)-related genes and other cancer-related genes, such as PPAR-γ, WNT5A, and TGF-β, in prostate cancer. ESS2 knockdown reduced nuclear factor (NF)-κB/CHD1 recruitment and histone H3K36me3 levels on the promoters of target genes (TNF and CCL2). In addition, we found that the transcriptional activities of NF-κB, NFAT and SMAD2/3 were enhanced by ESS2. Tamoxifen-inducible Ess2-knockout mice showed delayed prostate development with hypoplasia and disruption of luminal cells in the ventral prostate. Overall, these findings identified ESS2 acts as a transcriptional coregulator in prostate cancer and ESS2 can be novel epigenetic therapeutic target for CRPC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins / genetics
Humans
Male
Mice
Mice, Nude
NF-kappa B / metabolism
Neoplastic Processes
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Prostate* / pathology
Prostatic Neoplasms, Castration-Resistant* / drug therapy

Substances

DNA-Binding Proteins
NF-kappa B
Poly(ADP-ribose) Polymerase Inhibitors