HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer

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Abstract

E3 ligase is widely reported to exert fundamental functions in cancers. Through rigorous bioinformatic analysis concentrating E3 ligases based on data from Genotype-Tissue Expression (GTEx) and data from The Cancer Genome Atlas (TCGA), HERC3 was indicated to be downregulated in colorectal cancer (CRC) and HERC3 downregulation showed poor overall survival (OS) and disease-free survival (DFS). Through qRT-PCR, western blotting and Immunohistochemistry (IHC), analytical results were validated based on tissues in Zhongshan hospital. Functionally, HERC3 was indicated to inhibit the migration, invasion and metastasis in vitro and in vivo through transwell assays, wound healing assays and vivo experiments. And HERC3 could regulate epithelial-mesenchymal transition (EMT) in CRC. Furthermore, immunoprecipitation (IP), coimmunoprecipitation (co-IP) and GST-pulldown assays indicated that HERC3 could directly interact with EIF5A2 in vitro and in vivo through the RCC1 domain in HERC3. And HERC3 could function as an E3 to promote the K27 and K48-linked ubiquitination degradation of EIF5A2 via the HECT domain in HERC3, besides, K47, K67, K85, and K121 in EIF5A2 were identified as ubiquitination sites. In addition, HERC3 was indicated to affect the migration, invasion and metastasis and further regulatE EMT via EIF5A2/TGF-/Smad2/3 signal. The present study may provide insight into the mechanism of EMT in CRC.

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Colorectal cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ann Goding Sauer … (2020)

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.

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Mdm2 promotes the rapid degradation of p53.

Y Haupt, R Maya, A Kazaz … (1997)

The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

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FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.

Markus Welcker, Bruce Clurman (2008)

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.

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Author and article information

Contributors

Ronggui Hu:

ORCID: http://orcid.org/0000-0002-3939-6087

coryhu00@gmail.com

Jianmin Xu:

ORCID: http://orcid.org/0000-0002-5462-8421

xujmin@aliyun.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 21 January 2022

Publication date PMC-release: 21 January 2022

Publication date Collection: January 2022

Volume: 13

Issue: 1

Electronic Location Identifier: 74

Affiliations

[1 ]GRID grid.413087.9, ISNI 0000 0004 1755 3939, Department of General Surgery, , Zhongshan Hospital, Fudan University, ; 200030 Shanghai, China

[2 ]GRID grid.507739.f, ISNI 0000 0001 0061 254X, State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, ; 200030 Shanghai, China

Author information

Zhiyuan Zhang http://orcid.org/0000-0003-0336-7783

Ronggui Hu http://orcid.org/0000-0002-3939-6087

Jianmin Xu http://orcid.org/0000-0002-5462-8421

Article

Publisher ID: 4511

DOI: 10.1038/s41419-022-04511-7

PMC ID: 8782983

PubMed ID: 35064108

SO-VID: 4d5dbe12-e829-4d63-9319-fc77f2e2bb4b

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 August 2021

Date revision received : 12 December 2021

Date accepted : 30 December 2021

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ScienceOpen disciplines: Cell biology

Keywords: ubiquitins,gastrointestinal cancer

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ScienceOpen disciplines: Cell biology

Keywords: ubiquitins, gastrointestinal cancer

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HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer

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Most cited references 32

Colorectal cancer statistics, 2020

Mdm2 promotes the rapid degradation of p53.

FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.

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