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

ABSTRACT: Aurora-A has attracted a great deal of interest as a potential therapeutic target. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis of their 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, in an interferon/Janus kinase-independent manner, suggesting an unconventional mechanism regulating STAT1 expression. 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 the CpG islands in the STAT1 promoter and STAT1 overexpression. Simultaneous silencing of Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting of Aurora-A and UHRF1 can be a promising therapeutic strategy for cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160037 | GEO | 2020/10/26

REPOSITORIES: GEO

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