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Regulation of sister chromatid cohesion by nuclear PD-L1
Jia Yu1, Bo Qin1,2, Ann M Moyer3
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
Abstract:
Programmed death ligand-1 (PD-L1 or B7-H1) is well known for its role in immune checkpoint regulation, but its function inside the tumor cells has rarely been explored. Here we report that nuclear PD-L1 is important for cancer cell sister chromatid cohesion. We found that depletion of PD-L1 suppresses cancer cell proliferation, colony formation in vitro, and tumor growth in vivo in immune-deficient NSG mice independent of its role in immune checkpoint. Specifically, PD-L1 functions as a subunit of the cohesin complex, and its deficiency leads to formation of multinucleated cells and causes a defect in sister chromatid cohesion. Mechanistically, PD-L1 compensates for the loss of Sororin, whose expression is suppressed in cancer cells overexpressing PD-L1. PD-L1 competes with Wing Apart-Like (WAPL) for binding to PDS5B, and secures proper sister chromatid cohesion and segregation. Our findings suggest an important role for nuclear PD-L1 in cancer cells independent of its function in immune checkpoint.
Insights
Nuclear programmed death ligand-1 (PD-L1) is crucial for cancer cell division, independent of immune regulation. PD-L1 deficiency impairs sister chromatid cohesion, hindering cancer cell proliferation and tumor growth.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Programmed death ligand-1 (PD-L1), also known as B7-H1, is primarily recognized for its role in immune checkpoint regulation.
- Its function within tumor cells, particularly in nuclear processes, remains largely unexplored.
Purpose of the Study:
- To investigate the non-immune functions of PD-L1 within cancer cells.
- To elucidate the role of nuclear PD-L1 in cancer cell proliferation and genome stability.
Main Methods:
- Depletion of PD-L1 in cancer cells using genetic techniques.
- Assessment of cancer cell proliferation, colony formation, and tumor growth in vivo (using immune-deficient NSG mice).
- Analysis of sister chromatid cohesion, cell cycle progression, and protein complex interactions (cohesin, Sororin, WAPL, PDS5B).
Main Results:
- PD-L1 depletion suppressed cancer cell proliferation, colony formation, and tumor growth, independent of immune checkpoint functions.
- Nuclear PD-L1 was identified as a subunit of the cohesin complex, essential for sister chromatid cohesion.
- PD-L1 deficiency resulted in multinucleated cells and defects in sister chromatid cohesion, compensating for Sororin loss.
- PD-L1 competes with WAPL for PDS5B binding, ensuring proper sister chromatid cohesion and segregation.
Conclusions:
- Nuclear PD-L1 plays a critical role in maintaining cancer cell sister chromatid cohesion and genome stability.
- This function is independent of PD-L1's established role in immune checkpoint regulation.
- Targeting nuclear PD-L1 may offer novel therapeutic strategies for cancer treatment by disrupting cell division.
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