SRC activates TAZ for intestinal tumorigenesis and regeneration

Area of Science:

• Molecular biology
• Oncology
• Gastroenterology

Background:

• Proto-oncogene tyrosine-protein kinase Src (cSRC) plays a role in colorectal cancer (CRC) and intestinal regeneration.
• The precise cellular mechanisms linking cSRC to these processes remain unclear.

Purpose of the Study:

• To investigate the role of transcriptional coactivator with PDZ binding domain (TAZ) in cSRC-mediated CRC development and intestinal regeneration.
• To elucidate the molecular mechanisms by which cSRC influences TAZ activity.

Main Methods:

• Investigated cSRC-TAZ interaction in CRC cell lines and a CRC mouse model (Apc^Min/+).
• Utilized gene knockdown, phosphorylation site mutation, and knockout mouse models (intestinal TAZ knockout).
• Assessed cell proliferation, wound healing, colony formation, tumor formation, and intestinal regeneration after γ-irradiation.

Main Results:

• cSRC directly phosphorylates TAZ at Tyr316, promoting its nuclear localization and TEAD4-mediated transcription.
• cSRC overexpression increased TAZ levels in CRC cells, while cSRC knockdown decreased them.
• TAZ phosphorylation is essential for CRC cell proliferation, wound healing, colony formation, and tumor growth.
• Activated SRC correlated with increased TAZ in CRC polyps, and TAZ depletion reduced polyp formation.
• Intestinal TAZ knockout mice exhibited impaired regeneration after irradiation.
• SRC activation and TAZ overexpression were significantly correlated in CRC patients.

Conclusions:

• TAZ is a key mediator of cSRC's role in colorectal cancer development.
• TAZ is essential for cSRC-driven intestinal tumor formation and regeneration processes.
• Targeting the cSRC-TAZ pathway could offer therapeutic strategies for CRC and intestinal repair.