Epigenetic mechanism and target therapy of UHRF1 protein complex in malignancies

Abstract

Ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) functions as an epigenetic regulator recruiting PCNA, DNMT1, histone deacetylase 1, G9a, SuV39H, herpes virus-associated ubiquitin-specific protease, and Tatinteractive protein by multiple corresponding domains of DNA and H3 to maintain DNA methylation and histone modifications. Overexpression of UHRF1 has been found as a potential biomarker in various cancers resulting in either DNA hypermethylation or global DNA hypomethylation, which participates in the occurrence, progression, and invasion of cancer. The role of UHRF1 in the reciprocal interaction between DNA methylation and histone modifications, the dynamic structural transformation of UHRF1 protein within epigenetic code replication machinery in epigenetic regulations, as well as modifications during cell cycle and chemotherapy targeting UHRF1 are evaluated in this study.

The histone and non-histone methyllysine reader activities of the UHRF1 tandem Tudor domain are dispensable for the propagation of aberrant DNA methylation patterning in cancer cells

“…We sought to determine whether this interaction was unique or whether other methyllysine reader domains compete for this non-histone interaction. Biotinylated LIG1 (118-130) , LIG1 (118-130) K126me0, LIG1 (118-130) K126me2, and H3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) K9me2 peptides were complexed with Cy5streptavidin and hybridized to protein domain microarrays [25] that displayed 308 GST-tagged reader domains ( Fig. 1a left, Additional file 1: Fig.…”

“…Isolated domains were characterized as GST fusions and full-length protein as an MBP fusion. FAM-H3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) K9me2, H3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) K9me2-FAM, and FAM-LIG1 (118-130) K126me2 were purchased from GenScript.…”

“…UHRF1 functions as a DNA methylation maintenance factor, a characteristic that is likely dependent on its catalytic activity toward multiple sites of mono-ubiquitination on histone H3 (UniProtKB, P68431) [ 8 , 13 , 14 ] and PCNA-associated factor (PAF15, UniProtKB Q15004) [ 15 ], which are bound by the ubiquitin-interacting motif (UIM) of DNA (cytosine-5)-methyltransferase 1 (DNMT1, UniProtKB P26358) [ 16 – 18 ]. While the oncogenic role of UHRF1 is emerging [ 19 , 20 ], efforts to antagonize UHRF1 function have been challenging. Thus, a deep understanding of the UHRF1 protein–protein interaction network may reveal novel ways to disrupt its molecular function as a DNA methylation regulator.…”

Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways

“…Several previous studies have shown that UHRF1 overexpression observed in many human cancers is a primary event in the initiation and the development of cancer through regulating several signaling pathways. 32 - 37 To investigate whether UHRF1 can enhance cell proliferation in Jurkat cells, we examined the effect of UHRF1 knockdown on cell viability. The knockdown of UHRF1 in Jurkat cells ( Figure 5A ) led to a considerable decrease in the cell viability ( Figure 5B ) mimicking the effect of TQ on cell viability as shown in Figure 1B .…”

TIP60 governs the auto-ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

“…UHRF1 and TIP60 are within the same epigenetic complex with other partners like DNMT1, USP7, HDAC1, PCNA (proliferating cell nuclear antigen) and G9a/EHMT2 (euchromatic histone-lysine N methyltransferase 2) [17,25,27,64,69]. Higher expression levels of UHRF1 are reported in most cancer types [4,70] and related to suppression of TSGs expression, tumor invasion, poor prognosis and resistance towards chemotherapy [4,71,72,73,74,75]. In contrast to UHRF1, TIP60 expression is low in cancer cells.…”