Abstract
The epigenetic factor UHRF1 regulates transcription by modulating DNA methylation and histone modification, and plays critical roles in proliferation, development, and tumorigenesis. Here, we show that Wnt/c-Myc signaling upregulates UHRF1, which in turn downregulates TUSC3, a candidate tumor suppressor gene that is frequently deleted or downregulated in several cancers. We also show that UHRF1-mediated downregulation of TUSC3 is required for the proliferation of colon cancer cells. Furthermore, we demonstrate that UHRF1 suppresses TUSC3 expression by interacting with methylated H3K14 and thereby suppressing the acetylation of H3K14 by the histone acetyltransferase KAT7. Our study provides evidence for the significance of UHRF1-KAT7-mediated regulation of histone methylation/acetylation in the proliferation of tumor cells and in a diverse set of biological processes controlled by Wnt/c-Myc signaling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bostick M, Kim JK, Estève P-O, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007;317:1760–4.
Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007;450:908–12.
Citterio E, Papait R, Nicassio F, Vecchi M, Gomiero P, Mantovani R, et al. Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Mol Cell Biol. 2004;24:2526–35.
Jenkins Y, Markovtsov V, Lang W, Sharma P, Pearsall D, Warner J, et al. Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell. 2005;16:5621–9.
Du Z, Song J, Wang Y, Zhao Y, Guda K, Yang S, et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci Signal. 2010;3:ra80.
Qin W, Leonhardt H, Spada F. Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. J Cell Biochem. 2011;112:439–44.
Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K, et al. Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature. 2013;502:249–53.
Li X-L, Xu J-H, Nie J-H, Fan S-J. Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells. Oncol Rep. 2012;28:375–83.
Unoki M, Kelly JD, Neal DE, Ponder BAJ, Nakamura Y, Hamamoto R. UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer. Br J Cancer. 2009;101:98–105.
Unoki M, Daigo Y, Koinuma J, Tsuchiya E, Hamamoto R, Nakamura Y. UHRF1 is a novel diagnostic marker of lung cancer. Br J Cancer. 2010;103:217–22.
Babbio F, Pistore C, Curti L, Castiglioni I, Kunderfranco P, Brino L, et al. The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene. 2012;31:4878–87.
Sabatino L, Fucci A, Pancione M, Carafa V, Nebbioso A, Pistore C, et al. UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. Oncogene. 2012;31:5061–72.
Taniue K, Kurimoto A, Sugimasa H, Nasu E, Takeda Y, Iwasaki K, et al. Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. Proc Natl Acad Sci USA. 2016;113:1273–8.
Sapountzi V, Côté J. MYST-family histone acetyltransferases: beyond chromatin. Cell Mol Life Sci. 2011;68:1147–56.
Kueh AJ, Dixon MP, Voss AK, Thomas T. HBO1 is required for H3K14 acetylation and normal transcriptional activity during embryonic development. Mol Cell Biol. 2011;31:845–60.
Saksouk N, Avvakumov N, Champagne KS, Hung T, Doyon Y, Cayrou C, et al. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol Cell. 2009;33:257–65.
Miotto B, Struhl K. Differential gene regulation by selective association of transcriptional coactivators and bZIP DNA-binding domains. Mol Cell Biol. 2006;26:5969–82.
Miotto B, Struhl K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev. 2008;22:2633–8.
Miotto B, Struhl K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol Cell. 2010;37:57–66.
Doyon Y, Cayrou C, Ullah M, Landry A-J, Côté V, Selleck W, et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006;21:51–64.
Iizuka M, Matsui T, Takisawa H, Smith MM. Regulation of replication licensing by acetyltransferase Hbo1. Mol Cell Biol. 2006;26:1098–108.
Georgiakaki M, Chabbert-Buffet N, Dasen B, Meduri G, Wenk S, Rajhi L, et al. Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription. Mol Endocrinol. 2006;20:2122–40.
Avvakumov N, Côté J. The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007;26:5395–407.
Zong H, Li Z, Liu L, Hong Y, Yun X, Jiang J, et al. Cyclin-dependent kinase 11(p58) interacts with HBO1 and enhances its histone acetyltransferase activity. FEBS Lett. 2005;579:3579–88.
Mishima Y, Miyagi S, Saraya A, Negishi M, Endoh M, Endo TA, et al. The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis. Blood. 2011;118:2443–53.
Lalonde M-E, Cheng X, Côté J. Histone target selection within chromatin: an exemplary case of teamwork. Genes Dev. 2014;28:1029–41.
Lalonde M-E, Avvakumov N, Glass KC, Joncas F-H, Saksouk N, Holliday M, et al. Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. Genes Dev. 2013;27:2009–24.
Feng Y, Vlassis A, Roques C, Lalonde M-E, González-Aguilera C, Lambert J-P, et al. BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. EMBO J. 2016;35:176–92.
Latham JA, Dent SYR. Cross-regulation of histone modifications. Nat Struct Mol Biol. 2007;14:1017–24.
Margueron R, Trojer P, Reinberg D. The key to development: interpreting the histone code? Curr Opin Genet Dev. 2005;15:163–76.
Rolando M, Sanulli S, Rusniok C, Gomez-Valero L, Bertholet C, Sahr T, et al. Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host Microbe. 2013;13:395–405.
Dang CV. MYC on the path to cancer. Cell. 2012;149:22–35.
Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev. 2008;22:2755–66.
Kress TR, Sabò A, Amati B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer. 2015;15:593–607.
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192–205.
Pronobis MI, Peifer M. Wnt signaling: the many interfaces of β-catenin. Curr Biol. 2012;22:R137–9.
Arbieva ZH, Banerjee K, Kim SY, Edassery SL, Maniatis VS, Horrigan SK, et al. High-resolution physical map and transcript identification of a prostate cancer deletion interval on 8p22. Genome Res. 2000;10:244–57.
Bashyam MD, Bair R, Kim YH, Wang P, Hernandez-Boussard T, Karikari CA, et al. Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia. 2005;7:556–62.
Cooke SL, Pole JCM, Chin S-F, Ellis IO, Caldas C, Edwards PAW. High-resolution array CGH clarifies events occurring on 8p in carcinogenesis. BMC Cancer. 2008;8:288.
Birnbaum DJ, Adélaïde J, Mamessier E, Finetti P, Lagarde A, Monges G, et al. Genome profiling of pancreatic adenocarcinoma. Genes Chromosomes Cancer. 2011;50:456–65.
Vaňhara P, Horak P, Pils D, Anees M, Petz M, Gregor W, et al. Loss of the oligosaccharyl transferase subunit TUSC3 promotes proliferation and migration of ovarian cancer cells. Int J Oncol. 2013;42:1383–9.
Fan X, Zhang X, Shen J, Zhao H, Yu X, Chen Y, et al. Decreased TUSC3 promotes pancreatic cancer proliferation, invasion and metastasis. PLoS ONE. 2016;11:e0149028.
Ferraro A, Schepis F, Leone V, Federico A, Borbone E, Pallante P, et al. Tumor suppressor role of the CL2/DRO1/CCDC80 gene in thyroid carcinogenesis. J Clin Endocrinol Metab. 2013;98:2834–43.
Walczak EM, Kuick R, Finco I, Bohin N, Hrycaj SM, Wellik DM, et al. Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. Mol Endocrinol. 2014;28:1471–86.
Pils D, Horak P, Vanhara P, Anees M, Petz M, Alfanz A, et al. Methylation status of TUSC3 is a prognostic factor in ovarian cancer. Cancer. 2013;119:946–54.
Pils D, Horak P, Gleiss A, Sax C, Fabjani G, Moebus VJ, et al. Five genes from chromosomal band 8p22 are significantly down-regulated in ovarian carcinoma: N33 and EFA6R have a potential impact on overall survival. Cancer. 2005;104:2417–29.
Jiang Z, Guo M, Zhang X, Yao L, Shen J, Ma G, et al. TUSC3 suppresses glioblastoma development by inhibiting Akt signaling. Tumour Biol. 2016. https://doi.org/10.1007/s13277-016-5072-4.
Zhang Y, Su H-J, Pan K-F, Zhang L, Ma J-L, Shen L, et al. Methylation status of blood leukocyte DNA and risk of gastric cancer in a high-risk Chinese population. Cancer Epidemiol Biomark Prev. 2014;23:2019–26.
Bookstein R, Bova GS, MacGrogan D, Levy A, Isaacs WB. Tumour-suppressor genes in prostatic oncogenesis: a positional approach. Br J Urol. 1997;79:28–36.
Ahuja N, Li Q, Mohan AL, Baylin SB, Issa J-PJ. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res. 1998;58:5489–94.
Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S, et al. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011;44:361–72.
De Vos M, El Ramy R, Quénet D, Wolf P, Spada F, Magroun N, et al. Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions. J Biol Chem. 2014;289:16223–38.
Voss AK, Thomas T. MYST family histone acetyltransferases take center stage in stem cells and development. Bioessays. 2009;31:1050–61.
Arita K, Isogai S, Oda T, Unoki M, Sugita K, Sekiyama N, et al. Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc Natl Acad Sci USA. 2012;109:12950–5.
Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, et al. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature. 2008;455:822–5.
Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE, Cheng X. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 2008;455:826–9.
Gelato KA, Tauber M, Ong MS, Winter S, Hiragami-Hamada K, Sindlinger J, et al. Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol Cell. 2014;54:905–19.
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.
Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci USA. 2000;97:228–33.
Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA. 1982;79:7824–7.
Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA. 1982;79:7837–41.
Kelleher DJ, Karaoglu D, Mandon EC, Gilmore R. Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties. Mol Cell. 2003;12:101–11.
Mohorko E, Glockshuber R, Aebi M. Oligosaccharyltransferase: the central enzyme of N-linked protein glycosylation. J Inherit Metab Dis. 2011;34:869–78.
Mohorko E, Owen RL, Malojčić G, Brozzo MS, Aebi M, Glockshuber R. Structural basis of substrate specificity of human oligosaccharyl transferase subunit N33/Tusc3 and its role in regulating protein N-glycosylation. Structure. 2014;22:590–601.
Maruyama Y, Kawamura Y, Nishikawa T, Isogai T, Nomura N, Goshima N. HGPD: human gene and protein database, 2012 update. Nucl Acids Res. 2012;40:D924–9.
Goshima N, Kawamura Y, Fukumoto A, Miura A, Honma R, Satoh R, et al. Human protein factory for converting the transcriptome into an in vitro-expressed proteome. Nat Methods. 2008;5:1011–7.
Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucl Acids Res. 2006;34:D108–10.
Taniue K, Oda T, Hayashi T, Okuno M, Akiyama T. A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis. EMBO Rep. 2011;12:682–9.
Taniue K, Kurimoto A, Takeda Y, Nagashima T, Okada-Hatakeyama M, Katou Y, et al. ASBEL –TCF3 complex is required for the tumorigenicity of colorectal cancer cells. Proc Natl Acad Sci. 2016;113:05938.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (Integrative Analysis and Regulation of Cellular Diversity, no. 17H06325 and Non-coding RNA neo-taxonomy, no. 15H01464) from MEXT, Japan, and Project for Cancer Research and Therapeutic Evolution (P-CREATE, no. 17cm0106103h0002) from the Japan Agency for Medical Research and Development.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Taniue, K., Hayashi, T., Kamoshida, Y. et al. UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells. Oncogene 39, 1018–1030 (2020). https://doi.org/10.1038/s41388-019-1032-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-019-1032-y
This article is cited by
-
Identification of Chromatin Regulatory Factors Related to Immunity and Treatment of Alzheimer’s Disease
Journal of Molecular Neuroscience (2023)
-
Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer
Clinical Epigenetics (2022)
-
Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation
Genes & Genomics (2022)
-
UHRF1 downregulation promotes T follicular helper cell differentiation by increasing BCL6 expression in SLE
Clinical Epigenetics (2021)
-
HBO1 overexpression is important for hepatocellular carcinoma cell growth
Cell Death & Disease (2021)