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Cancer Biology & Therapy Volume 25, 2024 - Issue 1
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Research Paper

Repression of the SUMO-conjugating enzyme UBC9 is associated with lowered double minutes and reduced tumor progression

Yusi Wanga Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Hongyan Zoua Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Wei Jia Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Min Huanga Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Benhui Youa Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Nan Suna Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Yuandong Qiaoa Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Peng Liua Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Lidan Xua Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Xuelong Zhanga Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Mengdi Caia Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Ye Kuangc Department of Gynecology and Obstetrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, ChinaView further author information
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Songbin Fua Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaView further author information
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Wenjing Suna Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaCorrespondence[email protected]
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Xueyuan Jiaa Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, ChinaCorrespondence[email protected]
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Jie Wua Laboratory of Medical Genetics, Harbin Medical University, Harbin, China;b Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, China;d Future Medical Laboratory, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, ChinaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0003-1525-7864View further author information
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Article: 2323768 | Received 30 Oct 2023, Accepted 22 Feb 2024, Published online: 11 Mar 2024
 
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ABSTRACT

Double minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets supporting the conclusion of this article are included within the article.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384047.2024.2323768

Additional information

Funding

This research was funded by Natural Science Foundation of Heilongjiang Province of China (LH2021H006) and HMU Marshal Initiative Funding (HMUMIF-21007).
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