Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1

Abstract

Cancer is one of the leading causes of death worldwide, and its incidence and mortality are increasing each year. Improved therapeutic strategies against cancer have progressed, but remain insufficient to invert this trend. Along with several other risk factors, abnormal genetic and epigenetic regulations play a critical role in the initiation of cellular transformation, as well as tumorigenesis. The epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is a multidomain protein with oncogenic abilities overexpressed in most cancers. Through the coordination of its multiple domains and other epigenetic key players, UHRF1 regulates DNA methylation and histone modifications. This well-coordinated dialogue leads to the silencing of tumor-suppressor genes (TSGs) and facilitates tumor cells' resistance toward anticancer drugs, ultimately promoting apoptosis escape and uncontrolled proliferation. Several studies have shown that the downregulation of UHRF1 with natural compounds in tumor cells induces the reactivation of various TSGs, inhibits cell growth, and promotes apoptosis. In this review, we discuss the underlying mechanisms and the potential of various natural and synthetic compounds that can inhibit/minimize UHRF1's oncogenic activities and/or its expression.

Keywords: DNA methylation; cancer; epidrugs; epigenetics; phytochemical; tumor-suppressor genes UHRF1.

Figure 1

Structure and functions of UHRF1 protein (isoform 1) in normal and cancer cells along with its interaction with the DNA genome and nuclear proteins. UHRF1 is a multidomain protein having ubiquitin-like domain (UBL), tandem Tudor domain (TTD), plant homeodomain (PHD), SET and RING-associated domain (SRA), and really interesting new gene domain (RING) in its structure. (a) (in blue) indicates the interaction of different nuclear proteins with the proposed domains of UHRF1. (b) (in grey) indicates the interaction of UHRF1 with DNA and histone proteins. The SRA domain of UHRF1 recognizes hemi-methylated DNA or anomalies in DNA structure (ICLs and DSBs). TTD, PHD, and RING domains of UHRF1 interact with the indicated amino acids in H3 histone proteins. (c) (in green) highlights the cellular functions of UHRF1 in normal cells. UHRF1 is implicated in DNA methylation maintenance by recruiting DNMT1, recognizing DNA damage and initiating the DNA damage response, and regulating the function and stability of nuclear proteins through ubiquitination. (d) (in red) indicates the role of UHRF1 in cancer cells. UHRF1 represses many tumor-suppressor genes by maintaining the hyper-methylation of their promoters. High levels of UHRF1 in cancer cells also promote genetic instability by destabilizing DNMT1, which induces global hypomethylation. Furthermore, increased levels of UHRF1 facilitate the repair of DNA damage induced by radio or chemotherapy, making cancer cells resistant to anticancer therapy.

Figure 2

Proposed closed and open conformations of UHRF1. The PBR region between the SRA and RING domains interacts with TTD, which prevents the interaction of TTD with H3K9me3 marks, thus keeping the UHRF1 in closed conformation. On the other hand, proteins like PIP5 and USP7 can interact with the PBR of UHRF1 and disrupt the association between PBR and TTD, allowing TTD to interact with H3K9 methylation marks, which renders the UHRF1 in an open conformation. This open conformation of UHRF1 is also promoted by the binding of the SRA domain with hemi-methylated DNA, particularly in the S phase of the cell cycle.