ELF5 drives angiogenesis suppression though stabilizing WDTC1 in renal cell carcinoma

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Abstract

Background

Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system. Angiogenesis is a main contributing factor for tumorigenesis. E74-like transcription factor 5 (ELF5) has been verified to participate in the progression of different cancers and can regulate angiogenesis. This study was aimed to explore the functions of ELF5 in RCC.

Methods

Bioinformatics tools were used to predict the expression of ELF5 in RCC. RT-qPCR was applied for testing ELF5 expression in RCC cells. Cell behaviors were evaluated by colony formation, CCK-8, and transwell assays. The tube formation assay was used for determining angiogenesis. Methylation-specific PCR (MSP) was utilized for measuring the methylation level of ELF5 in RCC cells. ChIP and luciferase reporter assays were applied for assessing the binding of ELF5 and ubiquitin-specific protease 3 (USP3). Co-IP and GST pull-down were utilized for detecting the interaction of WD40 and tetratricopeptide repeats 1 (WDTC1) and USP3. Ubiquitination level of WDTC1 was determined by ubiquitination assay.

Results

ELF5 was lowly expressed in RCC cells and tissues. High expression of ELF5 expression notably suppressed RCC cell proliferative, migratory, and invasive capabilities, and inhibited angiogenesis. The tumor growth in mice was inhibited by ELF5 overexpression. ELF5 was highly methylated in RCC samples, and DNA methyltransferases (DNMTs) can promote hypermethylation level of ELF5 in RCC cells. ELF5 was further proved to transcriptionally activate USP3 in RCC. Moreover, USP3 inhibited WDTC1 ubiquitination. ELF5 can promote USP3-mediated WDTC1 stabilization. Additionally, WDTC1 silencing reversed the functions of ELF5 overexpression on RCC progression.

Conclusion

Downregulation of ELF5 due to DNA hypermethylation inhibits RCC development though the USP3/WDTC1axis in RCC.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12943-023-01871-2.

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Most cited references 54

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Cancer Statistics, 2021

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2021)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

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DNA methylation and its basic function.

Lisa Moore, Thuc Le, Guoping Fan (2013)

In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.

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Author and article information

Contributors

Yanzi Yang: yangyanzi@zcmu.edu.cn

Yue Gu: yuegu@ahmu.edu.cn

Jie Zhang: zhangj23@cslg.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 18 November 2023

Publication date PMC-release: 18 November 2023

Publication date Collection: 2023

Volume: 22

Electronic Location Identifier: 184

Affiliations

[1 ]School of Biology and Food Engineering, Changshu Institute of Technology, ( https://ror.org/05g6ben79) 99 Southern Sanhuan Road, Suzhou, 215500 China

[2 ]Wuxi School of Medicine, Jiangnan University, ( https://ror.org/04mkzax54) Wuxi, 214013 China

[3 ]Department of Pathology, The Second Affiliated Hospital of Soochow University, ( https://ror.org/02xjrkt08) Suzhou, 215000 China

[4 ]School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, ( https://ror.org/04epb4p87) Hangzhou, 310053 China

[5 ]GRID grid.186775.a, ISNI 0000 0000 9490 772X, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, , Anhui Medical University, ; 81 Meishan Road, Hefei, 230032 China

Article

Publisher ID: 1871

DOI: 10.1186/s12943-023-01871-2

PMC ID: 10656961

PubMed ID: 37980532

SO-VID: 500270df-d199-4b6f-8d79-222bfbe035c3

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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 15 August 2023

Date accepted : 26 September 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;

Award ID: BK20221091

Funded by: General Program of China Postdoctoral Science Foundation

Award ID: 2022M711369

Funded by: National Natural Science Foundation of China

Award ID: 82204392

Funded by: Natural Science Foundation of the Anhui Education Department

Award ID: KJ2021A0239

Funded by: Anhui Medical University Fund for Young Scientists Start-up Grant

Funded by: Suzhou Science and Technology Council

Award ID: SNG201907

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: renal cell carcinoma,elf5,wdtc1,usp3,angiogenesis,dna methylation

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: renal cell carcinoma, elf5, wdtc1, usp3, angiogenesis, dna methylation

ELF5 drives angiogenesis suppression though stabilizing WDTC1 in renal cell carcinoma

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

Related collections

Cancer Immunotherapy

Most cited references 54

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Cancer Statistics, 2021

DNA methylation and its basic function.

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