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Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes

Oncogene (2024)Cite this article

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Abstract

Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.

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Fig. 1: A SR-SRCC case of 11-year-old boy with novel inherited X-linked KDM6AA649T mutation.
Fig. 2: KDM6AA694T mutant have impaired H3K27me3 demethylase activity.
Fig. 3: KDM6AA694T mutant promotes tumor growth and metastasis.
Fig. 4: The KDM6AA694T mutant suppresses inflammatory macrophage response.
Fig. 5: RNA-seq analysis revealed that Jurkat cells expressing KDM6AA694T displayed suppressed effector T cell response.
Fig. 6: T cells expressing KDM6AA694T were incompetent to launch effector T-cell response.
Fig. 7: working model.

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Data availability

The raw sequencing data have been deposited in the Chinese National Genomics Data Center (accession code HRA002692).

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Acknowledgements

This research was supported by grant from National Natural Science Foundation of China (32070918 from JW), Outstanding Youth Fund of Guangdong Province (2022B1515020109 from JW), Start-up funding for the Pediatric Research Institute of Guangzhou Women and Children’s Medical Center (3001082 from JW), Natural Science Foundation of Shandong (ZR202110280038 from MF), Postdoctoral Innovation Project of Shandong Province (SDCX-ZG-202203028 from MF) and Municipal School (College) Joint Funding Project (202201020594 from CC and 202201020591 from QW). Finally, we sincerely thank BioRender (https://biorender.com/) for the elements within the experimental design diagram and graphical abstract.

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Author notes

  1. These authors contributed equally: Maoxiao Feng, Chengwei Chai, Xiaodong Hao, Xiaojiang Lai.

Authors and Affiliations

  1. Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Maoxiao Feng, Chengwei Chai, Xiaojiang Lai, Wenzhu Tang, Ningxin Gao, Guihong Pan, Xiaojie Liu, Wenjing Xiong & Qiang Wu

  2. Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China

    Maoxiao Feng & Yunshan Wang

  3. Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Chengwei Chai, Yuanyuan Luo, Hong Zhang & Qiang Wu

  4. Department of Pediatric General Surgery, Guangdong Women and Children Hospital, Guangzhou, 511442, China

    Chengwei Chai

  5. Department of Clinical Laboratory, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, 253000, China

    Xiaodong Hao

  6. Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

    Jun Wang

  7. The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Jun Wang

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Contributions

JW, QW and CC conceived the study cooperatively. JW and MF designed the research strategy. QW, CC, YL, and HZ provided the human tissue and blood samples and necessary interpretation of the clinical data. MF, XH and WX performed most of the experiments and data analysis with the help from Xiaojiang Lai, Xiaojie Liu and WT. WT performed the pedigree analysis of WES sequencing data. NG and GP finished the work of filing and deposition of the human genetic data. JW, MF and WX wrote the manuscript with constructive suggestions from QW and CC.

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Correspondence to Chengwei Chai, Wenjing Xiong, Qiang Wu or Jun Wang.

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Feng, M., Chai, C., Hao, X. et al. Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes. Oncogene (2024). https://doi.org/10.1038/s41388-024-03029-w

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