Targeting microRNA/UHRF1 pathways as a novel strategy for cancer therapy

Abstract

Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat-interacting protein 60 and histone methyltransferases G9a and Suv39H1. UHRF1 is considered to control a large macromolecular protein complex termed epigenetic code replication machinery, in order to maintain epigenetic silencing of TSGs during cell division, thus enabling cancer cells to escape apoptosis. MicroRNAs (miRNAs) are able to regulate the expression of its target gene by functioning as either an oncogene or a tumor suppressor. In the present review, the role of tumor suppressive miRNAs in the regulation of UHRF1, and the importance of targeting the microRNA/UHRF1 pathways in order to induce the reactivation of silenced TSGs and subsequent apoptosis are discussed.

Keywords: DNA methylation; apoptosis; cancer; epigenetics; microRNA; tumor suppressor genes; ubiquitin-like with PHD and RING finger domains 1.

Figure 1.

Schematic model of UHRF1 structure and its role in the regulation of the epigenetic code (DNA methylation and histone modifications). Through its SRA domain, UHRF1 interacts with DNMT1 and HDAC1. Using its PHD domain, UHRF1 may interact with the histone methyltransferase G9a and also with DNMT1. UHRF1 may be autoubiquitinated by its RING domain, encompassing an E3 ligase activity. By its interaction with HAUSP, UHRF1 may be protected from autoubiquitination. The TTD is involved in histone methylation reading with the subsequent recruitment of the histone methyltransferases G9a and Suv39H1. The UBL domain may be involved in the proteasome pathway. The question mark represents a putative interaction that requires further confirmation. SRA, SET- and RING-associated; DNMT1, DNA methyltransferase 1; HDAC1, histone deacetylase 1; PHD, plant homeodomain; RING, really interesting new gene; UHRF1, ubiquitin-like with PHD and RING finger domains 1; HUASP, herpesvirus-associated ubiquitin-specific protease; TTD, tandem Tudor domain; UBL, ubiquitin-like; Tip60, Tat-interacting protein 60; UB, ubiquitin.

Figure 2.

Schematic representation of the role of miRNA in UHRF1 regulation in different types of cancer cell: (A) Gastric cancer, (B) bladder cancer, (C) clear cell renal cell carcinoma, (D) colorectal cancer and (E) non-small cell lung cancer. Several tumor suppressor miRNAs are able to bind to the 3′-UTR of UHRF1 mRNA. This binding induces UHRF1 mRNA degradation and leads to the reactivation of several TSGs including Slit3, CDH4, RUNX3, PRDM2 and TP53 or to the inhibition of the expression of certain oncogenes including BIRC5 and CENPF. Question marks indicate putative effects that require further confirmation. UHRF1, ubiquitin-like with PHD and RING finger domains 1; TSG, tumor suppressor gene; Slit3, slit homolog 3 protein; CHD4, cadherin 4; RUNX3, runt-related transcription factor 3; PRDM2, PR domain zinc finger protein 2; BIRC5, survivin; CENPF, centromere protein F; miR, microRNA.