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GLTSCR1 deficiency promotes colorectal cancer development through regulating non-homologous end joining

Oncogene volume 43, pages 3517–3531 (2024)Cite this article

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Abstract

Non-homologous end joining (NHEJ), as one major pathway of DNA double-strand break (DSB) repair, could cause genomic instability, which plays pivotal roles in cancer development. While, chromatin remodeling complexes dictate the selection and orchestration of DSB repair pathways by regulating chromatin dynamics. However, the crosstalk between NHEJ and chromatin remodeling in cancer progress remains unclear. In this study, deficiency of GLTSCR1 causes resistance to DNA damage in colorectal cancer (CRC) cells by promoting NHEJ repair efficiency. Mechanistically, GLTSCR1 interacts with BRD9 to engage in the assembly of the non-canonical BAF complex (GBAF). However, GLTSCR1 deficiency disrupts GBAF and triggers the ubiquitination degradation of BRD9. Furthermore, GLTSCR1 deficiency causes aberrant opening in the promoter region of NHEJ repair-associated genes, which promotes CRC development. While, GLTSCR1 and its binding partner BRD9 are not directly involved in assembling NHEJ repair machinery; instead, they regulate the DNA accessibility of NHEJ repair-associated genes. Collectively, our findings confirm GLTSCR1 deficiency as a critical regulatory event of the NHEJ pathway in CRC development, which might require different therapeutic strategy for GLTSCR1 wild-type and mutant CRC.

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Fig. 1: GLTSCR1 deficiency resistance to DNA damage.
Fig. 2: GLTSCR1 deficiency promotes NHEJ repair efficiency.
Fig. 3: GLTSCR1 regulates NHEJ through participating in a unique SWI/SNF subcomplex.
Fig. 4: GLTSCR1 regulates the protein stability of BRD9.
Fig. 5: BB domain of GLTSCR1 binds to BRD9 and trans-locates BRD9 into the nucleus.
Fig. 6: BRD9 is required for NHEJ activity.
Fig. 7: GLTSCR1 regulates NHEJ depends on BRD9.
Fig. 8: Loss of GLTSCR1 promotes CRC development through upregulating the NHEJ pathway.

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Data availability

The data generated in this study are available within the article and its supplementary information files. The raw data of the ATAC-seq and RNA-seq data is available in SRA: PRJNA1099778.

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Acknowledgements

We thank Qiong Huang from the core facility platform of Zhejiang University School of Medicine for technical support. We thank the Laboratory Animal Center of Zhejiang University for technical assistance with management of mice.

Funding

This work was supported by National Natural Science Foundation of China (grants 81871937, 82472952 and 82173223), the CAMS Innovation Fund for Medical Sciences (CIFMS, grant number 2019-I2M-5-044) and the Guangdong Basic and Applied Basic Research Foundation (grant number 2023A1515140182).

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Author notes

  1. These authors contributed equally: Fengyan Han, Xiaoxu Zhou.

Authors and Affiliations

  1. Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China

    Fengyan Han, Lu Liu, Enping Xu & Honghe Zhang

  2. School of Basic Medical Science, The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Fengyan Han

  3. Women’s Reproductive Health Key Laboratory of Zhejiang Province, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China

    Xiaoxu Zhou

  4. Department of Pathology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China

    Beibei Yang

  5. Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China

    Pengyuan Liu

  6. Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, 322000, China

    Zhe Tang

  7. Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Zhe Tang

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Contributions

Conceptualization, HZ, FH, EX and ZT; methodology, FH, XZ, and LL; investigation, BY, PL and LL; writing—original draft, FH, XZ; writing—review & editing, HZ, FH, EX and ZT; funding acquisition, HZ and FH; resources, HZ and FH; Supervision, HZ and FH and all authors have approved the final version of the manuscript.

Corresponding authors

Correspondence to Fengyan Han, Enping Xu, Zhe Tang or Honghe Zhang.

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The authors declare no competing interests.

Ethics approval and consent to participate

All methods in this study were performed in accordance with the Declaration of Helsinki and its subsequent revisions. Colorectal carcinoma samples from patients in this study were collected from the Run Run Shaw Hospital, Zhejiang University. All participating patients were informed. The study was approved by the Ethic Committee of Zhejiang University, school of Medicine (Approval number: 2018‐018) and informed consent was obtained from every participant.

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Han, F., Zhou, X., Liu, L. et al. GLTSCR1 deficiency promotes colorectal cancer development through regulating non-homologous end joining. Oncogene 43, 3517–3531 (2024). https://doi.org/10.1038/s41388-024-03179-x

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