RUNX1 Regulates MCM2/CDC20 to Promote COAD Progression Modified by Deubiquitination of USP31

Overview

Journal Sci Rep

Specialty Science

Date 2024 Jun 17

PMID 38886545

Authors

Wei Tian

Jingyuan Zhao

Xinyu Zhang

Pengfei Li

Xuening Li

Yuan Hong

Shuai Li

Affiliations

Soon will be listed here.

Abstract

Colon adenocarcinoma (COAD) is the second leading cause of cancer death, and there is still a lack of diagnostic biomarkers and therapeutic targets. In this study, bioinformatics analysis of the TCGA database was used to obtain RUNX1, a gene with prognostic value in COAD. RUNX1 plays an important role in many malignancies, and its molecular regulatory mechanisms in COAD remain to be fully understood. To explore the physiological role of RUNX1, we performed functional analyses, such as CCK-8, colony formation and migration assays. In addition, we investigated the underlying mechanisms using transcriptome sequencing and chromatin immunoprecipitation assays. RUNX1 is highly expressed in COAD patients and significantly correlates with survival. Silencing of RUNX1 significantly slowed down the proliferation and migratory capacity of COAD cells. Furthermore, we demonstrate that CDC20 and MCM2 may be target genes of RUNX1, and that RUNX1 may be physically linked to the deubiquitinating enzyme USP31, which mediates the upregulation of RUNX1 protein to promote transcriptional function. Our results may provide new insights into the mechanism of action of RUNX1 in COAD and reveal potential therapeutic targets for this disease.

References

Lin T . RUNX1 and cancer. Biochim Biophys Acta Rev Cancer. 2022; 1877(3):188715. DOI: 10.1016/j.bbcan.2022.188715. View

Deng L, Meng T, Chen L, Wei W, Wang P . The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther. 2020; 5(1):11. PMC: 7048745. DOI: 10.1038/s41392-020-0107-0. View

Ye S, Lawlor M, Rivera-Reyes A, Egolf S, Chor S, Pak K . YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis. Cancer Res. 2018; 78(10):2705-2720. PMC: 6314302. DOI: 10.1158/0008-5472.CAN-17-4052. View

Liu B, Ruan J, Chen M, Li Z, Manjengwa G, Schluter D . Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases. Mol Psychiatry. 2021; 27(1):259-268. DOI: 10.1038/s41380-021-01233-8. View

Antao A, Tyagi A, Kim K, Ramakrishna S . Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics. Cancers (Basel). 2020; 12(6). PMC: 7352412. DOI: 10.3390/cancers12061579. View

Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini M . Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2020; 22(9):998-1009. DOI: 10.2174/1389450121999201117115717. View

Sood R, Kamikubo Y, Liu P . Role of RUNX1 in hematological malignancies. Blood. 2017; 129(15):2070-2082. PMC: 5391618. DOI: 10.1182/blood-2016-10-687830. View

Goyama S, Huang G, Kurokawa M, Mulloy J . Posttranslational modifications of RUNX1 as potential anticancer targets. Oncogene. 2014; 34(27):3483-92. DOI: 10.1038/onc.2014.305. View

Bae S . Tour d'Horizon of Recent Advances in RUNX Family Gene Research. Mol Cells. 2020; 43(2):97-98. PMC: 7057838. DOI: 10.14348/molcells.2020.2320. View

10.

Lu C, Yang Z, Yu D, Lin J, Cai W . RUNX1 regulates TGF-β induced migration and EMT in colorectal cancer. Pathol Res Pract. 2020; 216(11):153142. DOI: 10.1016/j.prp.2020.153142. View

11.

Scheitz C, Tumbar T . New insights into the role of Runx1 in epithelial stem cell biology and pathology. J Cell Biochem. 2012; 114(5):985-93. PMC: 5788165. DOI: 10.1002/jcb.24453. View

12.

Ito Y, Bae S, Chuang L . The RUNX family: developmental regulators in cancer. Nat Rev Cancer. 2015; 15(2):81-95. DOI: 10.1038/nrc3877. View

13.

Sun T, Liu Z, Yang Q . The role of ubiquitination and deubiquitination in cancer metabolism. Mol Cancer. 2020; 19(1):146. PMC: 7529510. DOI: 10.1186/s12943-020-01262-x. View

14.

Li Q, Lai Q, He C, Fang Y, Yan Q, Zhang Y . RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer. J Exp Clin Cancer Res. 2019; 38(1):334. PMC: 6670220. DOI: 10.1186/s13046-019-1330-9. View

15.

Vuik F, Nieuwenburg S, Bardou M, Lansdorp-Vogelaar I, Dinis-Ribeiro M, Bento M . Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut. 2019; 68(10):1820-1826. PMC: 6839794. DOI: 10.1136/gutjnl-2018-317592. View

16.

Chen S, Liu Y, Zhou H . Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors. Int J Mol Sci. 2021; 22(9). PMC: 8123678. DOI: 10.3390/ijms22094546. View

17.

La Vecchia S, Sebastian C . Metabolic pathways regulating colorectal cancer initiation and progression. Semin Cell Dev Biol. 2019; 98:63-70. DOI: 10.1016/j.semcdb.2019.05.018. View

18.

Park H, Baek K . E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer. 2022; 1877(3):188736. DOI: 10.1016/j.bbcan.2022.188736. View

19.

Tzimas C, Michailidou G, Arsenakis M, Kieff E, Mosialos G, Hatzivassiliou E . Human ubiquitin specific protease 31 is a deubiquitinating enzyme implicated in activation of nuclear factor-kappaB. Cell Signal. 2005; 18(1):83-92. DOI: 10.1016/j.cellsig.2005.03.017. View

20.

Sobolev V, Khashukoeva A, Evina O, Geppe N, Chebysheva S, Korsunskaya I . Role of the Transcription Factor FOSL1 in Organ Development and Tumorigenesis. Int J Mol Sci. 2022; 23(3). PMC: 8835756. DOI: 10.3390/ijms23031521. View