The inhibitory effect of human DEFA5 in growth of gastric cancer by targeting BMI1

• Published in: Cancer science 2021-03, Vol.112 (3), p.1075-1083
• Main Authors: Wu, Zhongwei, Ding, Zhaohui, Cheng, Bo, Cui, Zongchao
• Format: Article
• Language: English
• Subjects: Adult; alpha-Defensins - genetics; alpha-Defensins - metabolism; Animals; Antibodies; Apoptosis; Bioinformatics; BMI1; Carcinogenesis - genetics; Cell adhesion & migration; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cloning; Cold; Colon cancer; Colorectal cancer; Colorectal carcinoma; Computational Biology; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p19 - genetics; DEFA5; Defensins; Down-Regulation; E coli; Female; G1 Phase Cell Cycle Checkpoints - genetics; Gastrectomy; Gastric cancer; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; HEK293 Cells; Humans; Immune system; Innate immunity; Lung cancer; Male; Mice; Mice, Nude; Middle Aged; Original; Plasmids; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Proteins; Renal cell carcinoma; Stomach - pathology; Stomach - surgery; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach Neoplasms - surgery; Tumor cell lines; tumor suppressor; Tumor suppressor genes; Tumorigenesis; Up-Regulation
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14827

Defensins, a class of small cysteine‐rich cationic polypeptides across cellular life, are identified as antimicrobial compounds that display direct antimicrobial and immune signaling activities that are involved in the host defense. In addition to their roles in the innate immune system, accumulating studies have reported that some members of defensins are expressed and involved in some cancer cells, such as colon cancer, colorectal cancer, lung cancer and renal cell carcinomas. However, the roles of α‐Defensin 5 (DEFA5) in tumorigenesis and development remain unknown. In the present study, bioinformatics analysis and quantitative PCR results showed that the expression level of DEFA5 was dramatically downregulated in human gastric cancer. Overexpression of human DEFA5 in gastric cancer cell lines SGC7901 and BGC823 effectively diminished cell proliferation and reduced the colony forming ability. Moreover, DEFA5 overexpression induced cell cycle arrest by significantly increasing the number of G1‐phase cells. Consistently, in vivo tumor formation experiments in nude mice showed the suppression of the tumor growth by DEFA5 overexpression, suggesting an inhibitory effect of DEFA5 in gastric cancer. Mechanistically, DEFA5 directly binds to BMI1, which subsequently decreased its binding at the CDKN2a locus and upregulated the expression of 2 cyclin‐dependent kinase inhibitors, p16 and p19. Taken together, we concluded that DEFA5 showed an inhibitory effect in gastric cancer cell growth and may serve as a potential tumor suppressor in gastric cancer. DEFA5 directly binds to BMI1, which subsequently decreased its binding at the CDKN2a locus and upregulated the expression of 2 cyclin‐dependent kinase inhibitors, p16 and p19.