Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Abstract

Graphical Abstract Highlights d UHRF1 maintains cancer-specific DNA methylation through its chromatin reader domains d PHD and SRA domain mutants phenocopy UHRF1 depletion to reverse DNA hypermethylation d Disrupting PHD or SRA domain functions impairs key oncogenic properties of CRC cells d The maintenance function of overexpressed UHRF1 in CRC has prognostic significance SUMMARY UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone-and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

“…The epigenetic regulator ubiquitin-like with plant homeodomain and RING finger domains 1 (Uhrf1; also known as Np95 in mice and ICBP90 in humans) serves as a nonredundant adapter protein for Dnmt1 during S phase, recruiting Dnmt1 to hemimethylated DNA to ensure maintenance of CpG methylation patterns as part of multiprotein gene-repressive complexes (33)(34)(35)(36). Uhrf1 also regulates de novo DNA methylation via recruitment of Dnmt3a and Dnmt3b to chromatin (37,38).…”

m6A-dependent glycolysis enhances colorectal cancer progression

“…Various epigenetic modifications, including DNA methylation, histone modification, microRNA, and long noncoding RNA regulation, may contribute to colorectal carcinogenesis [43][44][45]. However, the potential involvement of RNA m 6 A modification is poorly defined in human colorectal cancer (CRC) and glycolytic metabolism.…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Besides, STAT3 induces UHRF1 expression via direct binding to its promoter. This is especially important in the context of cancer biology as the PHD and SRA domains of UHRF1 are involved in silencing the tumor suppressor genes in CRC cells [33]. The hallmarks of cancer coordinated by the STAT3-dependent transcriptional regulation of target proteins directly underpin the cellular responses.…”