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

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...

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Published inOncogene Vol. 43; no. 23; pp. 1757 - 1768
Main Authors Feng, Maoxiao, Chai, Chengwei, Hao, Xiaodong, Lai, Xiaojiang, Luo, Yuanyuan, Zhang, Hong, Tang, Wenzhu, Gao, Ningxin, Pan, Guihong, Liu, Xiaojie, Wang, Yunshan, Xiong, Wenjing, Wu, Qiang, Wang, Jun
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 07.06.2024
Nature Publishing Group
Subjects
13/21
13/31
14/1
38/23
38/91
631/250/580
631/67/327
Abdomen
Apoptosis
Birth defects
Cancer
Cell Biology
Cell growth
Cell proliferation
Children
Colorectal carcinoma
Demethylation
Disease
Hospitals
Human Genetics
Inflammation
Internal Medicine
Leukocyte migration
Lung cancer
Lymphocytes
Lymphocytes T
Macrophages
Malignancy
Medical laboratories
Medical prognosis
Medicine
Medicine & Public Health
Metastases
Metastasis
Mutants
Mutation
Oncology
Ostomy
Pathogenesis
Pediatrics
Proteins
Tumor suppressor genes
Tumors
Womens health
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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 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.
AbstractList 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.
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.
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.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.
Author Liu, Xiaojie
Zhang, Hong
Hao, Xiaodong
Wang, Jun
Wu, Qiang
Feng, Maoxiao
Lai, Xiaojiang
Pan, Guihong
Luo, Yuanyuan
Wang, Yunshan
Chai, Chengwei
Tang, Wenzhu
Gao, Ningxin
Xiong, Wenjing
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Snippet 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...
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springer
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StartPage 1757
SubjectTerms 13/21
13/31
14/1
38/23
38/91
631/250/580
631/67/327
Abdomen
Apoptosis
Birth defects
Cancer
Cell Biology
Cell growth
Cell proliferation
Children
Colorectal carcinoma
Demethylation
Disease
Hospitals
Human Genetics
Inflammation
Internal Medicine
Leukocyte migration
Lung cancer
Lymphocytes
Lymphocytes T
Macrophages
Malignancy
Medical laboratories
Medical prognosis
Medicine
Medicine & Public Health
Metastases
Metastasis
Mutants
Mutation
Oncology
Ostomy
Pathogenesis
Pediatrics
Proteins
Tumor suppressor genes
Tumors
Womens health
Title Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes
URI https://link.springer.com/article/10.1038/s41388-024-03029-w
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Volume 43
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