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

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 Daskalos A, "UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer" 117 : 1027-1037, 2011

2 Taniue K, "UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells" 39 : 1018-1030, 2020

3 Zhou L, "UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation" 16 : 1241-1251, 2015

4 Wang F, "UHRF1 promotes cell growth and metastasis through repression of p16(ink(4)a)in colorectal cancer" 19 : 2753-2762, 2012

5 Bostick M, "UHRF1 plays a role in maintaining DNA methylation in mammalian cells" 317 : 1760-1764, 2007

6 Wan X, "UHRF1 overexpression is involved in cell proliferation and biochemical recurrence in prostate cancer after radical prostatectomy" 35 : 34-, 2016

7 Unoki M, "UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer" 101 : 98-105, 2009

8 Kofunato Y, "UHRF1 expression is upregulated and associated with cellular proliferation in colorectal cancer" 28 : 1997-2002, 2012

9 Gorrini C, "Tip60 is a haplo-insufficient tumour suppressor required for an oncogeneinduced DNA damage response" 448 : 1063-1067, 2007

10 Squatrito M, "Tip60 in DNA damage response and growth control : many tricks in one HAT" 16 : 433-442, 2006

11 Heinrich R, "The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene" 279 : 5708-5715, 2004

12 Pan J, "Suppression of cell-cycle progression by Jun dimerization protein-2(JDP2)involves downregulation of cyclin-A2" 29 : 6245-6256, 2010

13 Zhang H, "SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1" 47 : 9053-9068, 2019

14 Arita K, "Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism" 455 : 818-821, 2008

15 Tsai MH, "Multiple functions of the histone chaperone Jun dimerization protein 2" 590 : 193-200, 2016

16 Hahm JY, "Methylation of UHRF1 by SET7 is essential for DNA double-strand break repair" 47 : 184-196, 2019

17 Ma H, "M phase phosphorylation of the epigenetic regulator UHRF1 regulates its physical association with the deubiquitylase USP7 and stability" 109 : 4828-4833, 2012

18 Ikura T, "Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis" 102 : 463-473, 2000

19 Idrissou M, "Exciting History of Tip60 and Its Companions in Carcinogenesis Across the Heterochromatin Landscapes" 22 : 626-628, 2018

20 Alhosin M, "Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties" 30 : 41-, 2011

21 Kong X, "Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties" 35 : 633-648, 2019

22 Sapountzi V, "Cellular functions of TIP60" 38 : 1496-1509, 2006

23 Siegel RL, "Cancer statistics, 2022" 72 : 7-33, 2022

24 Zhang ZM, "An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1" 12 : 1400-1406, 2015

25 Wang J, "Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation" 11 : 786-, 2020

26 Hahm JY, "Acetylation of UHRF1 Regulates Hemi-methylated DNA Binding and Maintenance of Genome-wide DNA Methylation" 32 : 107958-, 2020

27 Wang L, "ASEB : a web server for KAT-specific acetylation site prediction" 40 : W376-379, 2012

28 Sun Y, "A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM" 102 : 13182-13187, 2005

29 Zhang H, "A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice" 7 : 10201-, 2016