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ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via purinergic signaling and is associated with metastasis in human cutaneous squamous cell carcinoma

ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via purinergic signaling and is associated with metastasis in human cutaneous squamous cell carcinoma
ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via purinergic signaling and is associated with metastasis in human cutaneous squamous cell carcinoma
Ultraviolet radiation (UVR) and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells (Tregs) promote cSCC carcinogenesis and in other solid tumors, infiltrating Tregs and CD8+
T cells express ENTPD1 (also known as CD39), an ecto-enzyme that catalyzes the rate-limiting step in converting extracellular ATP to extracellular adenosine. We previously demonstrated that extracellular purine nucleotides influence DNA Damage Repair (DDR). Here we investigate whether DDR is modulated via purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared to T cells from blood or non-lesional skin and accordingly, concentrations of derivative extracellular ADP, AMP, and adenosine are increased in tumors compared to normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize compared to those that are non-metastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL27-dependent manner. Finally, increased extracellular adenosine is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DDR secondary to UVR. Together, these data suggest a novel role for ENTPD1 expression on skin-resident T cells to regulate DDR via purinergic signaling to promote skin carcinogenesis and metastasis.
0022-202X
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Melodi Javid Whitley
Jutamas Suwanpradid
Simon Jiang
Jonathan L. Cook
Daniel E. Zelac
Ross Rudolph
David L.Corcoran
Simone Degan
Ivan Spasojevic
Howard Levinson
Detlev Erdmann
Claire Reid
Jennifer Y. Zhang
Simon C. Robson,
Wendy L. Havran
Amanda S. MacLeod
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd

Lai, Chester and Healy, Eugene , Melodi Javid Whitley, Jutamas Suwanpradid, Simon Jiang, Jonathan L. Cook, Daniel E. Zelac, Ross Rudolph, David L.Corcoran, Simone Degan, Ivan Spasojevic, Howard Levinson, Detlev Erdmann, Claire Reid, Jennifer Y. Zhang, Simon C. Robson,, Wendy L. Havran and Amanda S. MacLeod (2021) ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via purinergic signaling and is associated with metastasis in human cutaneous squamous cell carcinoma. Journal of Investigative Dermatology. (doi:10.1016/j.jid.2021.02.753).

Record type: Article

Abstract

Ultraviolet radiation (UVR) and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells (Tregs) promote cSCC carcinogenesis and in other solid tumors, infiltrating Tregs and CD8+
T cells express ENTPD1 (also known as CD39), an ecto-enzyme that catalyzes the rate-limiting step in converting extracellular ATP to extracellular adenosine. We previously demonstrated that extracellular purine nucleotides influence DNA Damage Repair (DDR). Here we investigate whether DDR is modulated via purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared to T cells from blood or non-lesional skin and accordingly, concentrations of derivative extracellular ADP, AMP, and adenosine are increased in tumors compared to normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize compared to those that are non-metastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL27-dependent manner. Finally, increased extracellular adenosine is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DDR secondary to UVR. Together, these data suggest a novel role for ENTPD1 expression on skin-resident T cells to regulate DDR via purinergic signaling to promote skin carcinogenesis and metastasis.

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Final version - ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via - Accepted Manuscript
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Email confirming acceptance on 7th February 2021 - ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via
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More information

Accepted/In Press date: 7 February 2021
Published date: 20 April 2021
Additional Information: Note that this is a dermatology publication (not a respiratory publication). Acknowledgments We thank Robert Streilein and Chuan-Yuan Li for their assistance with experiments and advice on data interpretation, respectively. We thank Russell P. Hall for assistance with tissue collection and regulatory approval as well as for advice on data interpretation. This work was funded in part by support from the Department of Duke Dermatology (to ASM). MJW received support through the Duke Office of Physician Scientist Development Technician Support Grant and the Duke-UNC Immunotherapy Training Grant. CL was funded by the Wellcome Trust Research Training Fellowship (100683/Z/12/Z) and the National Institute for Health Research Clinical Lecturship. SWJ received support through the Burroughs Wellcome Fund Physician-Scientist Institutional Award.

Identifiers

Local EPrints ID: 450933
URI: http://eprints.soton.ac.uk/id/eprint/450933
ISSN: 0022-202X
PURE UUID: 18aae876-4f0a-4eec-a0ba-ab1997722ca1

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Date deposited: 24 Aug 2021 17:01
Last modified: 26 Nov 2021 00:03

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Contributors

Author: Chester Lai
Author: Eugene Healy
Corporate Author: Melodi Javid Whitley
Corporate Author: Jutamas Suwanpradid
Corporate Author: Simon Jiang
Corporate Author: Jonathan L. Cook
Corporate Author: Daniel E. Zelac
Corporate Author: Ross Rudolph
Corporate Author: David L.Corcoran
Corporate Author: Simone Degan
Corporate Author: Ivan Spasojevic
Corporate Author: Howard Levinson
Corporate Author: Detlev Erdmann
Corporate Author: Claire Reid
Corporate Author: Jennifer Y. Zhang
Corporate Author: Simon C. Robson,
Corporate Author: Wendy L. Havran
Corporate Author: Amanda S. MacLeod

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