Research ArticleCancer Biology

DNMT1 Stability Is Regulated by Proteins Coordinating Deubiquitination and Acetylation-Driven Ubiquitination

Sci. Signal.  02 Nov 2010:
Vol. 3, Issue 146, pp. ra80
DOI: 10.1126/scisignal.2001462

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Silencing the Silencer

DNA methylation of cytosines in CpG islands in gene promoters is associated with transcriptional silencing, and aberrant DNA methylation patterns can contribute to carcinogenesis through the inappropriate silencing of genes encoding tumor suppressors. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns, and its abundance is increased in various cancers; however, the mechanisms that control the abundance of DNMT1 were not well understood. Du et al. have identified proteins that regulate DNMT1 stability through the posttranslational modifications of acetylation and ubiquitination. The authors found that acetylation of DNMT by Tip60 promoted its ubiquitination by the E3 ligase UHRF1 and, consequently, its proteasomal degradation. In contrast, deubiquitination by HAUSP and deacetylation by HDAC1 increased DNMT1 abundance. The abundance of DNMT1 and HAUSP correlated in human colon cancers, and colorectal cancer cells lacking HAUSP were more sensitive to HDAC inhibitors in vitro and in tumor xenografts. These results suggest that combining a HAUSP inhibitor with an HDAC inhibitor may be an effective therapeutic combination to treat cancers.

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