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.
Highlights
Cancer is one of the main causes of death among Westernized countries and is principally due to environmental risk factors, including diet [1]
We have shown that UHRF1 represses the expression of tumour suppressor genes such as p16INK4A &RB1 leading to a down-regulation of the Vascular Endothelial Growth Factor (VEGF, Figure 2A) [49] and by a feedback mechanism, UHRF1 may be regulated by other tumour suppressor genes such as p53 and p73 products [46,67]
Natural compounds such as TQ, red wine polyphenols (RWPs) and potentially others (Figure 4) are triggering a series of events that involve cell cycle arrest, apoptosis and inhibition of angiogenesis, all under the control of UHRF1
Summary
Cancer is one of the main causes of death among Westernized countries and is principally due to environmental risk factors, including diet [1]. It has been shown that apple polyphenols has potent DNA demethylation activity in colorectal cancers by reducing DNMT1 expression with a subsequent activation of TSGs such as hMLH1, p14ARF and p16INK4A These genes are known to be silenced through their promoter hypermethylation in colorectal cancers [98]. A phase I pilot study showed that chronic intake of black raspberries by patients suffering from colorectal cancers leads to down-regulation of DNMT1 and re-expression of TSGs through a DNA demethylating process [104] This suggests that a therapeutically-induced inhibition of UHRF1 activity or expression could prevent the action of its preferred partners, HDAC1 and DNMT1, leading to a re-expression of the tumour suppressor genes p16INK4A and allowing the cancer cells to undergo apoptosis
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