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Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model
Published on: October 16, 2017
PRMT1 reverts the immune escape of necroptotic colon cancer through RIP3 methylation
Lian Zhang1,2,3,4, Yujiao He1, Yi Jiang2
1Medical Research Institute, Guangdong Cardiovascular Institute, Guangdong Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Abstract:
Necroptosis plays a double-edged sword role in necroptotic cancer cell death and tumor immune escape. How cancer orchestrates necroptosis with immune escape and tumor progression remains largely unclear. We found that RIP3, the central activator of necroptosis, was methylated by PRMT1 methyltransferase at the amino acid of RIP3 R486 in human and the conserved amino acid R479 in mouse. The methylation of RIP3 by PRMT1 inhibited the interaction of RIP3 with RIP1 to suppress RIP1-RIP3 necrosome complex, thereby blocking RIP3 phosphorylation and necroptosis activation. Moreover, the methylation-deficiency RIP3 mutant promoted necroptosis, immune escape and colon cancer progression due to increasing tumor infiltrated myeloid-derived immune suppressor cells (MDSC), while PRMT1 reverted the immune escape of RIP3 necroptotic colon cancer. Importantly, we generated a RIP3 R486 di-methylation specific antibody (RIP3ADMA). Clinical patient samples analysis revealed that the protein levels of PRMT1 and RIP3ADMA were positively correlated in cancer tissues and both of them predicted the longer patient survival. Our study provides insights into the molecular mechanism of PRMT1-mediated RIP3 methylation in the regulation of necroptosis and colon cancer immunity, as well as reveals PRMT1 and RIP3ADMA as the valuable prognosis markers of colon cancer.
Insights
PRMT1 methylates RIP3, inhibiting necroptosis and promoting colon cancer immune escape. This methylation, identified by a RIP3ADMA antibody, serves as a valuable prognostic marker for longer patient survival.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Necroptosis, a form of programmed cell death, has a complex role in cancer, influencing both cell death and immune evasion.
- The precise mechanisms by which cancer cells manipulate necroptosis for immune escape and tumor progression are not fully understood.
Purpose of the Study:
- To elucidate the role of RIP3 methylation by PRMT1 in regulating necroptosis, immune escape, and colon cancer progression.
- To identify potential prognostic biomarkers for colon cancer.
Main Methods:
- Investigated the interaction between PRMT1 methyltransferase and RIP3.
- Utilized a methylation-deficient RIP3 mutant to study its effects on necroptosis and immune cells.
- Developed a specific antibody (RIP3ADMA) to detect RIP3 di-methylation at R486.
- Analyzed clinical patient samples to correlate PRMT1 and RIP3ADMA levels with patient survival.
Main Results:
- PRMT1 methylates RIP3 at R486 (human) / R479 (mouse), inhibiting RIP1-RIP3 necrosome formation and necroptosis activation.
- Methylation-deficiency RIP3 mutant enhanced necroptosis, immune escape, and colon cancer progression by increasing myeloid-derived suppressor cells (MDSC).
- PRMT1 reversed immune escape in RIP3 necroptotic colon cancer.
- High levels of PRMT1 and RIP3ADMA in patient tissues correlated positively and predicted longer survival.
Conclusions:
- PRMT1-mediated RIP3 methylation is a key regulator of necroptosis and colon cancer immunity.
- PRMT1 and the RIP3ADMA antibody are promising prognostic biomarkers for colon cancer.
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