SYTL4 acts as a tumor suppressor in colorectal cancer by promoting ubiquitination and degradation of SEC31B.
TL;DR
The results delineate the SYTL4-SEC31B axis as a pivotal regulatory pathway in CRC tumorigenesis, which provides a promising candidate therapeutic target for colorectal cancer clinical intervention.
Abstract
Colorectal cancer (CRC) pathogenesis involves complex alterations in tumor suppressor genes and oncogenes. Although ubiquitin-mediated proteolysis represents a well-established regulatory mechanism, the functions of many E3 ubiquitin ligases in CRC remain poorly characterized. In this study, we identified the Rab effector SYTL4 (Synaptotagmin Like 4) as a potential uncharacterized E3 ubiquitin ligase with tumor-suppressive properties in colorectal cancer. Integrated analysis of TCGA and CPTAC datasets, validated with our clinical samples, demonstrated that lower SYTL4 protein abundance correlates strongly with unfavorable clinical outcomes of CRC patients. Functional analyses revealed that SYTL4 overexpression potently suppresses CRC cell proliferation, clonogenicity, and xenograft tumor growth. We identified SEC31B, a structural subunit of COPII vesicle coats, as the primary downstream mediator governed by SYTL4. We further showed that SYTL4 directly interacts with SEC31B and functions as an E3 ubiquitin ligase to trigger K48-type polyubiquitination of SEC31B and subsequent proteasome-dependent degradation. SEC31B exhibited intrinsic oncogenic properties, and its overexpression counteracted the tumor-suppressive effects of SYTL4. Collectively, our results delineate the SYTL4-SEC31B axis as a pivotal regulatory pathway in CRC tumorigenesis, which provides a promising candidate therapeutic target for colorectal cancer clinical intervention.