Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth

Area of Science:

• Molecular Biology
• Cancer Research
• Metabolic Pathways

Background:

• Tumor cells exhibit increased glucose uptake, a metabolic hallmark of cancer.
• Splicing dysregulation is recognized as a key feature in cancer development.
• The precise role of splicing factors in cancer-associated glucose metabolism is not well understood.

Purpose of the Study:

• To investigate the role of splicing factor SRSF5 in glucose metabolism and tumor progression.
• To elucidate the molecular mechanisms linking glucose intake, splicing, and cancer cell growth.
• To explore the potential of the SRSF5-CCAR1 pathway as a therapeutic target.

Main Methods:

• Investigated SRSF5 regulation by Tip60-mediated acetylation and Smurf1-mediated ubiquitylation in response to glucose availability.
• Analyzed the alternative splicing of CCAR1 induced by SRSF5, leading to CCAR1S and CCAR1L isoforms.
• Examined SRSF5 and CCAR1 expression in human lung cancer tissues and correlated findings with tumor progression.

Main Results:

• Glucose intake induces SRSF5 acetylation and stability, promoting CCAR1 alternative splicing to produce tumor-promoting CCAR1S.
• Glucose starvation leads to SRSF5 deacetylation and degradation, resulting in CCAR1L accumulation and apoptosis.
• SRSF5 is upregulated and hyperacetylated in human lung cancers, correlating with increased CCAR1S and tumor progression.

Conclusions:

• SRSF5 acts as a glucose-responsive splicing regulator that promotes tumor growth.
• The SRSF5-CCAR1 axis represents a critical link between glucose metabolism and cancer development.
• Targeting the SRSF5-CCAR1 pathway holds promise for novel cancer therapeutic strategies.