Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties

Abstract

Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.

Figure 1

Schematic representation of UHRF1 with the structural domains facing either DNA or histones. Abbreviation: UBL, Ubiquitin-like domain; TTD, cryptic Tandem Tudor Domain; PHD, Plant Homeo Domain; SRA, Set and Ring Associated; RING, Really Interesting New Gene. The major partners of UHRF1, namely Tat-Interactive Protein of 60 kDA (Tip60), DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a (G9a) and Histone DeAcetylase (HDAC1) are also depicted.

Figure 2

Schematic model of the role of UHRF1/DNMT1 complex in the regulation of p16^INK4A and VEGF gene expressions. A. When the SRA domain of UHRF1 meets hemi-methylated DNA present in the p16^INK4A promoter, UHRF1 acts as a guide for DNMT1 to methylate the complementary DNA strand. Subsequently a p16^INK4A gene repression and VEGF gene activation are maintained on the DNA daughter strands, i.e., in the daughter cancer cells. B. The UHRF1 down-regulation, by natural compounds such as TQ or polyphenols, induces the DNMT1 abundance decrease, that is accompanied by a p16^INK4A gene re-expression and a down-regulation of VEGF gene expression.

Figure 3

Schematic representation of RWPs-induced apoptosis involving p73 and UHRF1 deregulation in Jurkat cells and in an in vivo colorectal cancer model. A. Schematic representation of RWPs-induced apoptosis involving p73 and UHRF1 deregulation in Jurkat cells. RWPs triggers production of reactive oxygen species (ROS) and putatively DNA damage. The activation of the p73 gene results in enhanced caspase 3 level inducing UHRF1 decrease with subsequent G1/S arrest and apoptosis. B. The pathway involved in vivo is similar to that observed in Jurkat cells by involving a down-regulation of UHRF1 with subsequent increase of p16^INK4A gene expression. The down-regulation of UHRF1 is probably driven by p53 and/or p53. This is leading to an inhibition of tumor vascularization as a consequence of the down-regulation of the VEGF gene expression.

Figure 4

Summary of the effects of natural products such as TQ and RWPs. These compounds are putative "regulators" of the epigenetic code inheritance, since they are able to target UHRF1 with a subsequent cell cycle arrest, apoptosis and tumor vascularization reduction. An open square containing a question mark, emphases the possibility that numerous other natural compounds can take the same pathways leading to apoptosis.