Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation

Kai Fu, Xin Sun, Eric M. Wier, Andrea Hodgson, Yue Liu, Cynthia L. Sears, Fengyi Wan

Research output: Contribution to journalArticle

Abstract

Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a ʼnuclear-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.

Original languageEnglish (US)
Article numbere15018
JournaleLife
Volume5
Issue number2016JULY
DOIs
StatePublished - Jul 25 2016

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DNA Damage
Colon
Carcinogenesis
Addison Disease
Cape Verde
Adenosine Diphosphate Ribose
Polymers
Inborn Errors Amino Acid Metabolism
Transcription
Colonic Neoplasms
Contraception Behavior
Cyclic AMP Receptor Protein
Signal transduction
Castration
Substrates
NF-kappa B
Tumor Burden
Mitosis
Transcriptional Activation
Signal Transduction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation. / Fu, Kai; Sun, Xin; Wier, Eric M.; Hodgson, Andrea; Liu, Yue; Sears, Cynthia L.; Wan, Fengyi.

In: eLife, Vol. 5, No. 2016JULY, e15018, 25.07.2016.

Research output: Contribution to journalArticle

Fu K, Sun X, Wier EM, Hodgson A, Liu Y, Sears CL et al. Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation. eLife. 2016 Jul 25;5(2016JULY). e15018. Available from, DOI: 10.7554/eLife.15018

Fu, Kai; Sun, Xin; Wier, Eric M.; Hodgson, Andrea; Liu, Yue; Sears, Cynthia L.; Wan, Fengyi / Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation.

In: eLife, Vol. 5, No. 2016JULY, e15018, 25.07.2016.

Research output: Contribution to journalArticle

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abstract = "Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a ʼnuclear-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.",
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