Thymoquinone Is a Multitarget Single Epidrug That Inhibits the UHRF1 Protein Complex

Abstract

Silencing of tumor suppressor genes (TSGs) through epigenetic mechanisms, mainly via abnormal promoter DNA methylation, is considered a main mechanism of tumorigenesis. The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1. In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex. We also speculate on the possibility that TQ might specifically target UHRF1, with subsequent regulatory effects on other partners.

Integrated bioinformatics analysis of potential biomarkers for pancreatic cancer

“…UHRF1 positively regulates gene expression and DNA topoisomerase (ATP hydrolyzing) activity, nuclear chromatin, and protein binding. Several studies have shown that UHRF1 influences apoptosis in cancer cells 40–42 . ASPM is involved in forebrain neuroblast division, neuron migration, mitotic spindle regulation, coordination of mitotic processes, and maintenance of neural progenitor cells 43 .…”

“…Several studies have shown that UHRF1 influences apoptosis in cancer cells. 40 , 41 , 42 ASPM is involved in forebrain neuroblast division, neuron migration, mitotic spindle regulation, coordination of mitotic processes, and maintenance of neural progenitor cells. 43 ASPM mutations have been implicated in microcephaly.…”

A Fast Ubiquitination of UHRF1 Oncogene Is a Unique Feature and a Common Mechanism of Thymoquinone in Cancer Cells

“…Nevertheless, the profound mechanisms of TQ's effects on the ubiquitination status of UHRF1 still require further investigation. Objectively, due to the underlying complexity of the mechanisms of the interaction between UHRF1 and several proteins, including HAUSP [57], further studies are needed to explore the detailed mechanisms by which UHRF1 is rapidly polyubiquitinated in cancer cells in response to TQ and how HAUSP could be involved in the process.…”

HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins

“…HAUSP is found in many protein complexes with different functions, including the “Epigenetic Code Replication Machinery,” ECREM. Indeed, HAUSP is a main partner of ECREM, a large macromolecular complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING) finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60 [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Growing evidence indicates that the silencing of tumor suppressor genes (TSGs) in tumors is the result of a coordinated in-depth dialogue between DNA methylation and various histone post-translational modifications (PTMs) [ 39 , 40 , 41 , 42 ].…”

“…Several reports have shown that a faithful inheritance of the epigenetic patterns (DNA methylation and histone PTMs) during cell division involves temporal and spatial control of the chromatin effector proteins mainly UHRF1 and DNMT1, which govern various epigenetic events [ 34 , 39 , 43 , 44 , 45 , 46 , 47 ]. Understanding the major factors regulating the expression and activity of chromatin effector proteins UHRF1 and DNMT1 could therefore unlock new secrets regarding the transmission of epigenetic patterns during cell division.…”