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

Maoxiao Feng; Chengwei Chai; Xiaodong Hao; Xiaojiang Lai; Yuanyuan Luo; Hong Zhang; Wenzhu Tang; Ningxin Gao; Guihong Pan; Xiaojie Liu; Yunshan Wang; Wenjing Xiong; Qiang Wu; Jun Wang

doi:10.1038/s41388-024-03029-w

Inherited KDM6A^A649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes

Oncogene. 2024 Apr 15. doi: 10.1038/s41388-024-03029-w. Online ahead of print.

Authors

Maoxiao Feng^#^{1

2}, Chengwei Chai^#^{3

4

5}, Xiaodong Hao^#⁶, Xiaojiang Lai^#¹, Yuanyuan Luo⁷, Hong Zhang⁷, Wenzhu Tang¹, Ningxin Gao¹, Guihong Pan¹, Xiaojie Liu¹, Yunshan Wang², Wenjing Xiong⁸, Qiang Wu^{9

10}, Jun Wang^{11

12}

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.
² Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
³ 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. 2018760140@gzhmu.edu.cn.
⁴ Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. 2018760140@gzhmu.edu.cn.
⁵ Department of Pediatric General Surgery, Guangdong Women and Children Hospital, Guangzhou, 511442, China. 2018760140@gzhmu.edu.cn.
⁶ Department of Clinical Laboratory, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, 253000, China.
⁷ Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
⁸ 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. fionawj215@163.com.
⁹ 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. wuqiangll@hotmail.com.
¹⁰ Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. wuqiangll@hotmail.com.
¹¹ 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. jwang03@sibs.ac.cn.
¹² The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. jwang03@sibs.ac.cn.

^# Contributed equally.

PMID: 38622203
DOI: 10.1038/s41388-024-03029-w

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 KDM6A^A694T 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 KDM6A^A694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6A^A694T 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 KDM6A^A694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6A^A694T 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.

Grants and funding

32070918/National Natural Science Foundation of China (National Science Foundation of China)