Targeted demethylation of the SARI promotor impairs colon tumour growth. (28th April 2019)

• Record Type: Journal Article
• Authors: Wang, Qin; Dai, Lei; Wang, Yuan; Deng, Jie; Lin, Yi; Wang, Qingnan; Fang, Chao; Ma, Zida; Wang, Huiling; Shi, Gang; Cheng, Lin; Liu, Yi; Chen, Shuang; Li, Junshu; Dong, Zhexu; Su, Xiaolan; Yang, Lie; Zhang, Shuang; Jiang, Ming; Huang, Meijuan; Yang, Yang; Yu, Dechao; Zhou, Zongguang; Wei, Yuquan; Deng, Hongxin
• Is Part Of: Cancer letters. Volume 448(2019)
• Page Start: 132
• Page End: 143
• Publication Date: 2019-04-28
• Subjects: Colon cancer -- SARI -- Methylation -- dCas9 -- TET1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.01.040
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: SARI (suppressor of activator protein 1, regulated by IFN) functions as a tumour suppressor and is inactivated in various cancers. However, the mechanism underlying SARI inactivation in cancer remains elusive. In this study, we detected a high level of DNA methylation of the SARI promoter and an inverse correlation between SARI promoter methylation and expression in malignant tissues from patients with colon cancer. Furthermore, we found that the SARI promoter methylation status is a prognostic indicator for patients with colon cancer. A dCas9-multiGCN4/scFv-TET1CD-sgRNA-based SARI -targeted demethylation system (dCas9-multiGCN4/scFv-TET1CD-sgSARI) was constructed to precisely and specifically demethylate regions of SARI ; this system resulted in the substantial activation of SARI expression. Further in vitro and in vivo data confirmed that dCas9-multiGCN4/scFv-TET1CD-sgSARI exerts anti-tumour effects by regulating tumour proliferation, apoptosis, and angiogenesis. Collectively, specific demethylation of the SARI promoter and restoration of endogenous SARI expression by dCas9-multiGCN4/scFv-TET1CD-SARI have therapeutic applications for colon cancer and perhaps for other cancers. Highlights: DNA methylation mediates SARI downregulation in colon cancer. SARI methylation predicts prognosis in colon cancer. Targeted demethylation of SARI was observed using dCas9-multiGCN4/scFv-TET1CD and sgSARIs Targeted demethylation of SARI impairs colon tumour progression.