Abstract

Zinc protein KLF13 is a tumor-suppressive member of Kruppel-like factors family, and yet the effect of KLF13 on gastric cancer has not been reported. Here, we aimed to investigate the role of KLF13 in gastric cancer and explored underlying molecular mechanisms. Firstly, it was found that KLF13 expression was significantly decreased in gastric cancer tissues and cancer cells compared with adjacent normal tissues and normal gastric epithelial cells, respectively. KEGG_Pathway and GO_BP analyses suggested that KLF13 was associated with CELL_CYCLE and CELL_PROLIFERATION. Then, our results further demonstrated that KLF13 could obviously inhibit gastric cancer proliferation and induce cell arrest at G2/M phase. Mechanistically, KLF13 decreased expressions of β-catenin and its target genes, CCND1 and MYC, via triggering autophagic degradation of β-catenin. KLF13 up-regulation facilitated co-localization and binding of β-catenin with autophagy protein p62, and exogenous overexpression of β-catenin or blocking autophagy process appeared to reverse KLF13-induced inhibition of gastric cancer proliferation. Furthermore, KLF13 overexpression promoted the expression of ubiquitin-conjugating enzyme E2, Ubc13 which is responsible for catalyzing the synthesis of 'Lys-63'-linked polyubiquitin chains and increased the binding of β-catenin with E3 ubiquitin ligase, TRAF6. In vivo, KLF13 overexpression also suppressed xenograft tumor growth of gastric cancer and down-regulated expressions of Ki67, β-catenin, Cyclin D1, and c-Myc in tumor tissues. Collectively, these data firstly demonstrated the involvement of KLF13 in inhibiting cell proliferation of gastric cancer through promoting autophagy-dependent degradation of β-catenin, which reinforced the evidence for suppressive roles of KLF13 in human tumors.