Acetylation of UHRF1 Regulates Hemi-methylated DNA Binding and Maintenance of Genome-wide DNA Methylation

Hahm, Ja Young; Park, Jin Woo; Kang, Joo-Young; Park, Jun-Young; Kim, Chulhong; Kim, Jiyoung; Ha, Nam‐Chul; Kim, Jung-Woong; Seo, Sang-Beom

doi:10.1016/j.celrep.2020.107958

Cited by 17 publications

(8 citation statements)

References 23 publications

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“…In the previous study, we showed that UHRF1 K490 acetylation through PCAF impairs hemi-methylated DNA binding of UHRF1 (Hahm et al 2020 ). To identify whether TIP60-mediated acetylation of UHRF1 could induce any physiological effect on HCT116 cells, we performed MTT assay and colony formation assay with shUHRF1 by comparing transfection of UHRF1 WT and 4KR mutant.…”

Section: Resultsmentioning

confidence: 94%

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Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation

et al. 2022

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Background Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is upregulated in colon cancer cells and associated with silencing tumor suppressor genes (TSGs) to promote colon cancer cell proliferation. Objective To investigate epigenetic modification of UHRF1 by TIP60. Whether UHRF1 acetylation by TIP60 can induce cell proliferation in colon cancer cells. Methods Acetylation sites of UHRF1 by TIP60 was predicted by ASEB (Acetylation Set Enrichment Based) method and identified by immunoprecipitation assay using anti-pan-acetyl lysine antibody and in vitro acetylation assay. Based on this method, UHRF1 acetylation-deficient mimic 4KR (K644R, K646R, K648R, K650R) mutant was generated to investigate effects of UHRF1 acetylation by TIP60. shRNA system was used to generate stable knockdown cell line of UHRF1. With transient transfection of UHRF1 WT and 4KR, the effects of UHRF1 4KR mutant on Jun dimerization protein 2 (JDP2) gene expression, cell proliferation and cell cycle were investigated by RT-qPCR and FACS analysis in shUHRF1 colon cancer cell line. Results Downregulation of TIP60-mediated UHRF1 acetylation is correlated with suppressed cell cycle progression. Acetylation-deficient mimic of UHRF1 showed poor cell growth through increased expression of JDP2 gene. Conclusions Acetylation of UHRF1 4K residues by TIP60 is important for colon cancer cell growth. Furthermore, upregulated JDP2 expression by acetylation-deficient mutant of UHRF1 might be an important epigenetic target for colon cancer cell proliferation.

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Section: Resultsmentioning

confidence: 94%

“…Previously, we identified that UHRF1 is acetylated by PCAF and inhibits its binding to hemi-methylated DNA in HCT116 cell line (Hahm et al 2020 ). Another study revealed that TIP60 acetylated UHRF1 at K659 (isoform 1, K644 at isoform 3) by in vitro acetylation assay (Zhang et al 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation

et al. 2022

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“…S6 c). Studies with mouse embryonic stem cells (mESCs) and colorectal cancer cells showed that knockdown of UHRF1 induced global DNA hypomethylation 32 , 53 , 54 . These results suggest the possibility that DNMT1 is predominant DNA methylation regulator in THP-1 cells which has more important roles in regulating global DNA methylation pattern than UHRF1 and DNMT3B.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages

Park,

Luo,

Park

et al. 2023

Sci Rep

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DNA methylation is an epigenetic modification that regulates gene expression and plays an essential role in hematopoiesis. UHRF1 and DNMT1 are both crucial for regulating genome-wide maintenance of DNA methylation. Specifically, it is well known that hypermethylation is crucial characteristic of acute myeloid leukemia (AML). However, the mechanism underlying how DNA methylation regulates the differentiation of AML cells, including THP-1 is not fully elucidated. In this study, we report that UHRF1 or DNMT1 depletion enhances the phorbol-12-myristate-13-acetate (PMA)-induced differentiation of THP-1 cells. Transcriptome analysis and genome-wide methylation array results showed that depleting UHRF1 or DNMT1 induced changes that made THP-1 cells highly sensitive to PMA. Furthermore, knockdown of UHRF1 or DNMT1 impeded solid tumor formation in xenograft mouse model. These findings suggest that UHRF1 and DNMT1 play a pivotal role in regulating differentiation and proliferation of THP-1 cells and targeting these proteins may improve the efficiency of differentiation therapy in AML patients.

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“…The acetylation of UHRF1 is crucial for the regulation of hemi-methylated DNA binding and maintenance of genome-wide DNA methylation. The acetylation of UHRF1 is regulated by P300/CBP-associated factor (PCAF) and HDAC1 [ 40 ]. Initially, UHRF1 is acetylated by PCAF at K490, thereby disrupting its binding to the hemi-methylated DNA in the nascent DNA.…”

Section: Ptms Of Uhrf1 Proteinmentioning

confidence: 99%

Roles of post-translational modifications of UHRF1 in cancer

Gu,

Fu,

2024

Epigenetics & Chromatin

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UHRF1 as a member of RING-finger type E3 ubiquitin ligases family, is an epigenetic regulator with five structural domains. It has been involved in the regulation of a series of biological functions, such as DNA replication, DNA methylation, and DNA damage repair. Additionally, aberrant overexpression of UHRF1 has been observed in over ten cancer types, indicating that UHRF1 is a typical oncogene. The overexpression of UHRF1 repressed the transcription of such tumor-suppressor genes as CDKN2A, BRCA1, and CDH1 through DNMT1-mediated DNA methylation. In addition to the upstream transcription factors regulating gene transcription, post-translational modifications (PTMs) also contribute to abnormal overexpression of UHRF1 in cancerous tissues. The types of PTM include phosphorylation, acetylation, methylationand ubiquitination, which regulate protein stability, histone methyltransferase activity, intracellular localization and the interaction with binding partners. Recently, several novel PTM types of UHRF1 have been reported, but the detailed mechanisms remain unclear. This comprehensive review summarized the types of UHRF1 PTMs, as well as their biological functions. A deep understanding of these crucial mechanisms of UHRF1 is pivotal for the development of novel UHRF1-targeted anti-cancer therapeutic strategies in the future.

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Acetylation of UHRF1 Regulates Hemi-methylated DNA Binding and Maintenance of Genome-wide DNA Methylation

Cited by 17 publications

References 23 publications

Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation

Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation

Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages

Roles of post-translational modifications of UHRF1 in cancer

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