Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1 ‐mediated DNA methylation mechanism

CagA gene transduction increases KLF4 promoter methylation level, which leads to inactivation of KLF4. Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1 ‐mediated DNA methylation mechanism. AbstractKr üppel‐like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report thatHelicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5 ‐hmC levels were lower in GC cells withH pylori infection than in GC cells withoutH pylori infection. Thus, our study not only sheds new light on howH pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in theH pylori/CagA ‐TET1‐KLF4 signaling pathw...

Source: Cancer Medicine - February 4, 2020 Category: Cancer & Oncology Authors: Rongrong Zhao, Zhengxia Liu, Wenting Xu, Le Song, Haifeng Ren, Yang Ou, Yakun Liu, Siying Wang Tags: ORIGINAL RESEARCH Source Type: research