Kiuchi Jun, Komatsu Shuhei, Imamura Taisuke, Nishibeppu Keiji, Shoda Katsutoshi, Arita Tomohiro, Kosuga Toshiyuki, Konishi Hirotaka, Shiozaki Atsushi, Kubota Takeshi, Okamoto Kazuma, Fujiwara Hitoshi, Ichikawa Daisuke, Tsuda Hitoshi, Otsuji Eigo
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan.
First Department of Surgery, Faculty of Medicine, University of Yamanashi Yamanashi, Japan.
Am J Cancer Res. 2018 Dec 1;8(12):2436-2452. eCollection 2018.
YEATS domain containing 4 (YEATS4) has functions of chromatin modification and transcriptional regulation and is in a gene-amplified region (12q13) in various human cancers. In this study, we tested whether YEATS4 acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). We analyzed 5 GC cell lines and 135 primary tumor samples of GC, which were curatively resected in our hospital. Overexpression of the YEATS4 protein was frequently detected in GC cell lines (5/5 cell lines, 100%) and primary GC tumor tissues (32/135 cases, 23.7%). Knockdown of YEATS4 inhibited proliferation, migration and invasion of GC cells through NOTCH2 down-regulation in a mutation-independent manner, and induced apoptosis in wild-type GC cells. Moreover, knockdown of YEATS4 improved chemosensitivity for CDDP and L-OHP. Overexpression of YEATS4 protein significantly correlated with more aggressive lymphatic invasion, larger tumor size, deeper tumor depth, positive lymph node metastasis and recurrence. Patients with YEATS4-overexpressing tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that YEATS4 was independently associated with poor outcomes. These findings suggest that YEATS4 plays a pivotal role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
含YEATS结构域蛋白4（YEATS4）具有染色质修饰和转录调控功能，且在多种人类癌症的基因扩增区域（12q13）中。在本研究中，我们检测了YEATS4在胃癌（GC）中是否通过其激活/过表达发挥促癌基因的作用。我们分析了本院根治性切除的5种GC细胞系和135例GC原发性肿瘤样本。在GC细胞系（5/5细胞系，100%）和原发性GC肿瘤组织（32/135例，23.7%）中经常检测到YEATS4蛋白的过表达。敲低YEATS4以不依赖突变的方式通过下调NOTCH2抑制GC细胞的增殖、迁移和侵袭，并诱导野生型GC细胞凋亡。此外，敲低YEATS4提高了对顺铂（CDDP）和奥沙利铂（L-OHP）的化疗敏感性。YEATS4蛋白的过表达与更具侵袭性的淋巴浸润、更大的肿瘤大小、更深的肿瘤深度、阳性淋巴结转移和复发显著相关。YEATS4过表达肿瘤患者的总生存率低于无表达肿瘤的患者。多变量分析表明，YEATS4与不良预后独立相关。这些发现表明，YEATS4通过其过表达在肿瘤恶性潜能中起关键作用，并突出了其作为GC预后因素和潜在治疗靶点的有用性。
