Nuclear PD-L1 regulates YAP-driven transcription via the PGE2-EP4-YAP-importin α3 axis in solid tumors
Satapathy, Shakti Ranjan LU
and Sjölander, Anita
LU
(2026)
In Cell Reports
45(2).
p.1-16
- Abstract
- Prostaglandin E2 (PGE2) is synthesized by cyclooxygenase 2 (COX-2) in the arachidonic acid pathway. PGE2 promotes cancer initiation and progression while facilitating chronic inflammation and immunosuppression, partly through regulation of programmed death ligand 1 (PD-L1) in tumor cells and tumor-associated macrophages. PGE2 also modulates Hippo signaling, enhancing nuclear Yes-associated protein-1 (YAP1) activity by preventing its phosphorylation-mediated degradation. However, whether PGE2 can similarly recruit PD-L1 into the nucleus has remained unexplored. Here, we show that PGE2 promotes the nuclear recruitment of PD-L1 in colon and breast cancer cells. Using nuclear co-immunoprecipitation and proximity ligation assays, we found that... (More)
- Prostaglandin E2 (PGE2) is synthesized by cyclooxygenase 2 (COX-2) in the arachidonic acid pathway. PGE2 promotes cancer initiation and progression while facilitating chronic inflammation and immunosuppression, partly through regulation of programmed death ligand 1 (PD-L1) in tumor cells and tumor-associated macrophages. PGE2 also modulates Hippo signaling, enhancing nuclear Yes-associated protein-1 (YAP1) activity by preventing its phosphorylation-mediated degradation. However, whether PGE2 can similarly recruit PD-L1 into the nucleus has remained unexplored. Here, we show that PGE2 promotes the nuclear recruitment of PD-L1 in colon and breast cancer cells. Using nuclear co-immunoprecipitation and proximity ligation assays, we found that PGE2 upregulates PD-L1 expression and facilitates its nuclear translocation through YAP and importin-α3. Nuclear PD-L1 (nPD-L1) enhances YAP-mediated transcriptional activity through TEAD-promoter engagement. YAP deficiency blocks PD-L1 nuclear localization, and importin-α3 knockdown prevents the nuclear translocation of both YAP and PD-L1. Pharmacological inhibition of the EP4 or COX-2 significantly reduces nPD-L1 levels. Collectively, our findings identify the PGE2-EP4-YAP-importin-α3 axis as a key regulator of PD-L1 nuclear transport and YAP-driven transcriptional programs. Targeting this pathway may suppress nPD-L1- and Hippo-dependent tumor growth, offering a therapeutic strategy for cancers with elevated YAP activity. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/448dceee-8ebf-4efc-a845-4e18eb4d2aa5
- author
- Satapathy, Shakti Ranjan
LU
and Sjölander, Anita
LU
- organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Reports
- volume
- 45
- issue
- 2
- article number
- 116963
- pages
- 1 - 16
- publisher
- Cell Press
- external identifiers
-
- pmid:41671087
- scopus:105031633131
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2026.116963
- language
- English
- LU publication?
- yes
- id
- 448dceee-8ebf-4efc-a845-4e18eb4d2aa5
- date added to LUP
- 2026-03-19 13:49:06
- date last changed
- 2026-06-27 18:00:19
@article{448dceee-8ebf-4efc-a845-4e18eb4d2aa5,
abstract = {{Prostaglandin E2 (PGE2) is synthesized by cyclooxygenase 2 (COX-2) in the arachidonic acid pathway. PGE2 promotes cancer initiation and progression while facilitating chronic inflammation and immunosuppression, partly through regulation of programmed death ligand 1 (PD-L1) in tumor cells and tumor-associated macrophages. PGE2 also modulates Hippo signaling, enhancing nuclear Yes-associated protein-1 (YAP1) activity by preventing its phosphorylation-mediated degradation. However, whether PGE2 can similarly recruit PD-L1 into the nucleus has remained unexplored. Here, we show that PGE2 promotes the nuclear recruitment of PD-L1 in colon and breast cancer cells. Using nuclear co-immunoprecipitation and proximity ligation assays, we found that PGE2 upregulates PD-L1 expression and facilitates its nuclear translocation through YAP and importin-α3. Nuclear PD-L1 (nPD-L1) enhances YAP-mediated transcriptional activity through TEAD-promoter engagement. YAP deficiency blocks PD-L1 nuclear localization, and importin-α3 knockdown prevents the nuclear translocation of both YAP and PD-L1. Pharmacological inhibition of the EP4 or COX-2 significantly reduces nPD-L1 levels. Collectively, our findings identify the PGE2-EP4-YAP-importin-α3 axis as a key regulator of PD-L1 nuclear transport and YAP-driven transcriptional programs. Targeting this pathway may suppress nPD-L1- and Hippo-dependent tumor growth, offering a therapeutic strategy for cancers with elevated YAP activity.}},
author = {{Satapathy, Shakti Ranjan and Sjölander, Anita}},
issn = {{2211-1247}},
language = {{eng}},
number = {{2}},
pages = {{1--16}},
publisher = {{Cell Press}},
series = {{Cell Reports}},
title = {{Nuclear PD-L1 regulates YAP-driven transcription via the PGE2-EP4-YAP-importin α3 axis in solid tumors}},
url = {{http://dx.doi.org/10.1016/j.celrep.2026.116963}},
doi = {{10.1016/j.celrep.2026.116963}},
volume = {{45}},
year = {{2026}},
}