RASSF4 inhibits cell proliferation and increases drug sensitivity in colorectal cancer through YAP/Bcl-2 pathway

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The RASSF family of proteins plays a role in human cancer development.
• The specific expression and function of RASSF4 in colorectal cancer (CRC) remain underexplored.

Purpose of the Study:

• To investigate the expression pattern of RASSF4 in colorectal cancer (CRC) tissues and cell lines.
• To elucidate the biological significance and molecular mechanisms of RASSF4 in CRC progression and 5-FU treatment response.

Main Methods:

• Immunohistochemistry on 118 CRC specimens and 30 normal colon tissues.
• TCGA dataset analysis for RASSF4 expression.
• Cell-based assays (growth, colony formation, cell cycle, apoptosis, mitochondrial potential) in LoVo cells with ectopic RASSF4 expression.
• Western blot, YAP knockdown, and ChIP assays to investigate molecular pathways.

Main Results:

• RASSF4 was significantly downregulated in CRC tissues compared to normal tissues, correlating with advanced TNM stage, T status, node positivity, and high Ki-67 index.
• Ectopic RASSF4 expression inhibited CRC cell proliferation, colony formation, and cell cycle progression, while increasing sensitivity to 5-FU.
• RASSF4 overexpression promoted 5-FU-induced apoptosis, reduced mitochondrial membrane potential, repressed YAP and Bcl-2, and upregulated p21.
• YAP knockdown abrogated RASSF4's effect on Bcl-2, and TEAD4 binding to the Bcl-2 promoter was confirmed.

Conclusions:

• RASSF4 is downregulated in human colorectal cancer and serves as a potential prognostic marker.
• RASSF4 regulates malignant behaviors in CRC cells, including proliferation and apoptosis, partly through the YAP/Bcl-2 signaling pathway.
• RASSF4 may represent a therapeutic target to enhance the efficacy of chemotherapy in CRC.