JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8
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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.
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.
Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC50 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.
Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.
KeywordsGastric cancer Histone lysine demethylases Jumonji domain-containing protein 2A (JMJD2A) Coiled-coil domain containing 8 (CCDC8) Drug resistance
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant number JP16K19348 and JP18K07942]. We thank Hideaki Horikawa for analysis of microarray data, supported by the Support Center for Advanced Medical Sciences, Tokushima University Graduate School of Biomedical Sciences.
Compliance with ethical standards
Conflict of interest
Tetsuji Takayama received a research fund from TAIHO Pharmaceutical Co., Ltd. (Tokyo, Japan).
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.
Informed consent or a substitute for it was obtained from all patients for being included in the study.
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