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: Research - peer-reviewArticle

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.

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

Fingerprint

Chemical activation
DNA
DNA Damage
Colon
Carcinogenesis
Adenosine Diphosphate Ribose
Polymers
Transcription
Colonic Neoplasms
Signal transduction
NF-kappa B
Tumors
Genes
Cells
RNA
Apoptosis
Substrates
Tumor Burden
Mitosis
Transcriptional Activation

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: Research - peer-reviewArticle

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. 2016 ; Vol. 5, No. 2016JULY.
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