JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8
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ORIGINAL ARTICLE
JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8 Tadahiko Nakagawa1,2 · Yasushi Sato3 · Toshihito Tanahashi1 · Yasuhiro Mitsui1 · Yoshifumi Kida1 · Yasuteru Fujino1 · Misato Hirata1 · Shinji Kitamura1 · Hiroshi Miyamoto1 · Koichi Okamoto1 · Naoki Muguruma1 · Yoshimi Bando4 · Tetsuji Takayama1 Received: 22 July 2019 / Accepted: 14 October 2019 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019
Abstract Background Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. Methods We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. Results Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the I C50 values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. Conclusions Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target. Keywords Gastric cancer · Histone lysine demethylases · Jumonji domain-containing protein 2A (JMJD2A) · Coiled-coil domain containing 8 (CCDC8) · Drug resistance
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-019-01024-9) contains supplementary material, which is available to authorized users. * Yasushi Sato sato.yasushi@tokushima‑u.ac.jp 1
2
Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770‑8503, Japan Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, Shimane 693‑8550, Japan
Histone lysine methylation is recognized as an important post-translational modi
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