Yoon Jung-Ho, Byun Hyojoo, Ivan Cristina, Calin George A, Jung Dahyun, Lee Sangkil
Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, Korea.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2022 May 11;14(10):2369. doi: 10.3390/cancers14102369.
DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation via interaction with EZH2 and is involved in the canonical Wnt signaling pathway. Additionally, interaction between UC.145 and another long non-coding RNA adjacent to DKK1, PRKG1-AS1, induced a synergistic effect on Wnt signaling. The regulation of these three genes was closely associated with patient overall survival. Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.
DKK1抑制已知参与多种癌症的经典Wnt信号通路。然而，DKK1是作为癌基因还是肿瘤抑制基因仍存在争议。此外，胃癌中DKK1的调控机制尚未明确。本研究的目的是探讨超保守区域UC.145是否调节胃癌中DKK1表达的表观遗传变化。微阵列分析显示，UC.145对组蛋白甲基转移酶EZH2表现出最高的结合亲和力。使用小干扰RNA（siRNA）在胃癌细胞系中评估UC.145失活的影响。结果表明，UC.145通过与EZH2相互作用触发DKK1甲基化，并参与经典Wnt信号通路。此外，UC.145与DKK1相邻的另一种长链非编码RNA PRKG1-AS1之间的相互作用对Wnt信号产生协同效应。这三个基因的调控与患者的总生存期密切相关。UC.145失活诱导胃癌细胞凋亡，并抑制其生长、迁移、侵袭和集落形成能力。该研究结果为胃癌中的Wnt信号提供了见解，并支持UC.145作为该疾病潜在的新型预测生物标志物。
