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. 2024 Dec 31;25(1):2323768.
doi: 10.1080/15384047.2024.2323768. Epub 2024 Mar 11.

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

Yusi Wang  1   2 , Hongyan Zou  1   2 , Wei Ji  1   2 , Min Huang  1   2 , Benhui You  1   2 , Nan Sun  1   2 , Yuandong Qiao  1   2 , Peng Liu  1   2 , Lidan Xu  1   2 , Xuelong Zhang  1   2 , Mengdi Cai  1   2 , Ye Kuang  3 , Songbin Fu  1   2 , Wenjing Sun  1   2 , Xueyuan Jia  1   2 , Jie Wu  1   2   4
Affiliations

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

Yusi Wang et al. Cancer Biol Ther. .

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.

Keywords: DNA damage repair; SUMOylation; UBC9; double minutes; genome instability.

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Conflict of interest statement

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

Figures

Figure 1.
Figure 1.
Higher expression of SUMOylation-related molecules are associated with increased genomic instability and double minute (DM) counts.
Figure 2.
Figure 2.
UBC9 knockdown is associated with lowered DMs and DM-carried gene expression.
Figure 3.
Figure 3.
UBC9 inhibition by the 2-D08 inhibitor yields similar results as UBC9 knockdown, due to reduced SUMOylation.
Figure 4.
Figure 4.
UBC9 knockdown reduces tumor malignancy and growth.
Figure 5.
Figure 5.
UBC9 inhibition in vivo decreases the rate of tumor growth, via eliminating DMs.
Figure 6.
Figure 6.
Lowered UBC9 activity is associated with increased micronucleus (MN) expulsion, DNA damage, and decreased DNA damage repair.
See this image and copyright information in PMC

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