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TRIM28 protects CARM1 from proteasome-mediated degradation to prevent colorectal cancer metastasis
Jinyuan Cui1, Jia Hu2, Zhilan Ye2
1Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract:
TRIM28 (Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer (CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1 (co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/β-catenin signaling in a CARM1-dependent manner, but independent of CARM1's methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/β-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.
Insights
Tripartite motif-containing protein 28 (TRIM28) suppresses colorectal cancer (CRC) metastasis by stabilizing CARM1 and inhibiting WNT/β-catenin signaling. Downregulation of TRIM28 indicates a poor prognosis in CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Tripartite motif-containing protein 28 (TRIM28) exhibits aberrant expression and diverse functions across human cancers.
- The specific roles and underlying mechanisms of TRIM28 in colorectal cancer (CRC) progression remain largely undefined.
Purpose of the Study:
- To elucidate the function and mechanism of TRIM28 in colorectal cancer (CRC).
- To investigate TRIM28's role as a prognostic factor in CRC.
- To identify key molecular pathways regulated by TRIM28 in CRC metastasis.
Main Methods:
- Analysis of TRIM28 expression in CRC tissues and correlation with clinical stages and patient outcomes.
- In vitro and in vivo functional assays to assess the impact of TRIM28 on CRC cell migration and invasion.
- Co-immunoprecipitation and proteasome degradation assays to determine the interaction between TRIM28 and CARM1.
- Western blotting and signaling pathway analysis (WNT/β-catenin) to investigate the molecular mechanism.
Main Results:
- TRIM28 expression was downregulated in CRC, particularly in advanced stages, correlating with a favorable prognosis.
- TRIM28 significantly inhibited CRC cell migration and invasion both in vitro and in vivo.
- TRIM28 physically interacted with and stabilized co-activator-associated arginine methyltransferase 1 (CARM1), preventing its proteasomal degradation.
- TRIM28 suppressed CRC metastasis by inhibiting WNT/β-catenin signaling in a CARM1-dependent manner, irrespective of CARM1's methyltransferase activity.
- High co-expression of TRIM28 and CARM1 correlated with improved patient survival, while low expression indicated poor outcomes.
Conclusions:
- TRIM28 functions as a tumor suppressor in colorectal cancer, inhibiting metastasis.
- The TRIM28-CARM1 axis plays a crucial role in regulating CRC cell invasion and metastasis via the WNT/β-catenin pathway.
- TRIM28 and CARM1 represent potential prognostic biomarkers and therapeutic targets for colorectal cancer treatment.
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