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

Area of Science:

• Molecular Biology
• Cellular Signaling
• Cancer Research

Background:

• Nuclear factor kappa B (NF-κB) transcription mediates cellular responses to DNA damage.
• The early nuclear signaling cascade linking DNA damage to NF-κB activation remains poorly understood.

Purpose of the Study:

• To identify key regulators of NF-κB activation in response to genotoxic stress.
• To elucidate the role of Sam68 in DNA damage signaling and colon tumorigenesis.

Main Methods:

• Investigated the role of Sam68/KHDRBS1 in genotoxic stress-initiated signaling pathways.
• Assessed the impact of Sam68 deficiency on DNA damage-stimulated PAR production and NF-κB transactivation.
• Utilized cell culture (human colon cancer cells) and mouse models (genetic deletion of Sam68).

Main Results:

• Sam68 deficiency abolished DNA damage-stimulated PAR production and PAR-dependent NF-κB transactivation of anti-apoptotic genes.
• Sam68-deficient cells exhibited hypersensitivity to genotoxic agents.
• Upregulated Sam68 correlated with elevated PAR production and NF-κB-mediated anti-apoptotic transcription in colon cancer.
• Sam68 knockdown sensitized colon cancer cells to genotoxic stress-induced apoptosis.
• Genetic deletion of Sam68 reduced colon tumor burden in mice.

Conclusions:

• Sam68 is a critical regulator of the NF-κB pathway in response to genotoxic stress.
• Sam68 plays a crucial role in promoting colon cancer cell survival and tumor growth by mediating PAR-dependent NF-κB signaling.
• Targeting Sam68 may represent a therapeutic strategy for colon cancer treatment.