Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation
Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-κB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-κB activation...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/15018 |
| _version_ | 1811180414142775296 |
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| author | Kai Fu Xin Sun Eric M Wier Andrea Hodgson Yue Liu Cynthia L Sears Fengyi Wan |
| author_facet | Kai Fu Xin Sun Eric M Wier Andrea Hodgson Yue Liu Cynthia L Sears Fengyi Wan |
| author_sort | Kai Fu |
| collection | DOAJ |
| description | Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-κB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-κB activation is poorly understood. Here we report that Src-associated-substrate-during-mitosis-of-68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) is a key NF-κB regulator in genotoxic stress-initiated signaling pathway. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-κB transactivation of anti-apoptotic genes. Sam68 deleted cells are hypersensitive to genotoxicity caused by DNA damaging agents. Upregulated Sam68 coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription in human and mouse colon cancer. Knockdown of Sam68 sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and genetic deletion of Sam68 dampens colon tumor burden in mice. Together our data reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is crucial for colon tumorigenesis. |
| first_indexed | 2024-04-11T09:02:45Z |
| format | Article |
| id | doaj.art-611381bba30b4a869c74157cc791d44b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:02:45Z |
| publishDate | 2016-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-611381bba30b4a869c74157cc791d44b2022-12-22T04:32:43ZengeLife Sciences Publications LtdeLife2050-084X2016-07-01510.7554/eLife.15018Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activationKai Fu0Xin Sun1https://orcid.org/0000-0003-2424-8011Eric M Wier2Andrea Hodgson3Yue Liu4Cynthia L Sears5Fengyi Wan6https://orcid.org/0000-0001-9216-9767Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, John Hopkins University, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesW. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, John Hopkins University, Baltimore, United States; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, United StatesNuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-κB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-κB activation is poorly understood. Here we report that Src-associated-substrate-during-mitosis-of-68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) is a key NF-κB regulator in genotoxic stress-initiated signaling pathway. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-κB transactivation of anti-apoptotic genes. Sam68 deleted cells are hypersensitive to genotoxicity caused by DNA damaging agents. Upregulated Sam68 coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription in human and mouse colon cancer. Knockdown of Sam68 sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and genetic deletion of Sam68 dampens colon tumor burden in mice. Together our data reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is crucial for colon tumorigenesis.https://elifesciences.org/articles/15018NF-kBcolon cancersignal transductionDNA damage responsesSam68KHDRBS1 |
| spellingShingle | Kai Fu Xin Sun Eric M Wier Andrea Hodgson Yue Liu Cynthia L Sears Fengyi Wan Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation eLife NF-kB colon cancer signal transduction DNA damage responses Sam68 KHDRBS1 |
| title | Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation |
| title_full | Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation |
| title_fullStr | Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation |
| title_full_unstemmed | Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation |
| title_short | Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation |
| title_sort | sam68 khdrbs1 is critical for colon tumorigenesis by regulating genotoxic stress induced nf κb activation |
| topic | NF-kB colon cancer signal transduction DNA damage responses Sam68 KHDRBS1 |
| url | https://elifesciences.org/articles/15018 |
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