Int J Med Sci 2021; 18(15):3437-3451. doi:10.7150/ijms.61969 This issue

Research Paper

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

Jing Han1,2*, Xin Chen1,2*, Jiawei Xu1,2,4*, Laili Chu3*, Rongqing Li1,2, Na Sun1,2, Zhen Jiang1,2,4, Hongyang Liu1,2,4, Xing Ge1,2, Junnian Zheng3,5✉, Jing Yang1,2✉, Takayuki Ikezoe6

1. Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
2. Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
3. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
4. National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
5. Department of Oncology, the first affiliated hospital, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
6. The Department of Hematology, Fukushima Medical University, Fukushima, Japan.
*These authors have contributed equally to this work.

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Citation:
Han J, Chen X, Xu J, Chu L, Li R, Sun N, Jiang Z, Liu H, Ge X, Zheng J, Yang J, Ikezoe T. Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1. Int J Med Sci 2021; 18(15):3437-3451. doi:10.7150/ijms.61969. Available from https://www.medsci.org/v18p3437.htm

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Abstract

Graphic abstract

Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.

Keywords: Aurora-A, UHRF1, STAT1, colorectal cancer cell