GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

Salvatore Rizza*, Luca Di Leo, Chiara Pecorari, Paola Giglio, Fiorella Faienza, Costanza Montagna, Emiliano Maiani, Michele Puglia, Francesca M. Bosisio, Trine Skov Petersen, Lin Lin, Vendela Rissler, Juan Salamanca Viloria, Yonglun Luo, Elena Papaleo, Daniela De Zio, Blagoy Blagoev, Giuseppe Filomeni

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Abstract

Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.

OriginalsprogEngelsk
Artikelnummer111997
TidsskriftCell Reports
Vol/bind42
Udgave nummer1
ISSN2211-1247
DOI
StatusUdgivet - 31. jan. 2023

Bibliografisk note

Funding Information:
We are grateful to Laila Fisher for her secretarial work. We would like to acknowledge Matteo Lambrughi, Maria Francesca Allega, and Emmanuelle Bignon for discussion and involvement in the early stages of FAK1 molecular modeling; Søs Grønbæk Holdgaard, Mette Vixø Vistesen, and Chloé Duculty for experimental support; and Vanda Turcanova for lab assistance. This work was supported by grants from the Danish Cancer Society (KBVU R146-A9414 and R231-A13855 to G.F., R204-A12424 to D.D.Z.), the Italian Association for Cancer Research ( IG2017-20719 to G.F.), the LEO Foundation ( LF-OC-19-000004 to D.D.Z.), and the Novo Nordisk Foundation ( NNF18OC0052550 to G.F., NNF18OC0052768 to B.B.). The work was also supported in part by the Danish National Research Foundation (DNRF; grant 141 to ATLAS) and the INTEGRa research infrastructure funded by NNF . D.D.Z. is supported by the Melanoma Research Alliance young investigator grant ( MRA 620385 ), C.P. is a recipient of a PhD fellowship from the Danish Cancer Research Foundation (Dansk Kraeft-forskningsfond, DKF-0-0-532 ), F.F. is supported by an AIRC Fellowship for Italy, and E.M. and C.M. are supported by Fondazione Umberto Veronesi . L.L. is supported by Independent Research Fund Denmark – Sapere Aude Starting Grant ( 8048-00072A ) and the Novo Nordisk Foundation ( NNF21OC0071718 ). CRISPR gene editing in the laboratory of Y.L. is partially supported by the European Union’s Horizon 2020 research and innovation program under grant agreement 899417 . Cancer Structural Biology, Redox Biology, and Melanoma Research Team labs are part of the Center of Excellence for Autophagy, Recycling and Disease (CARD), funded by Danmarks Grundforskningsfond ( DNRF125 ).

Funding Information:
We are grateful to Laila Fisher for her secretarial work. We would like to acknowledge Matteo Lambrughi, Maria Francesca Allega, and Emmanuelle Bignon for discussion and involvement in the early stages of FAK1 molecular modeling; Søs Grønbæk Holdgaard, Mette Vixø Vistesen, and Chloé Duculty for experimental support; and Vanda Turcanova for lab assistance. This work was supported by grants from the Danish Cancer Society (KBVU R146-A9414 and R231-A13855 to G.F. R204-A12424 to D.D.Z.), the Italian Association for Cancer Research (IG2017-20719 to G.F.), the LEO Foundation (LF-OC-19-000004 to D.D.Z.), and the Novo Nordisk Foundation (NNF18OC0052550 to G.F. NNF18OC0052768 to B.B.). The work was also supported in part by the Danish National Research Foundation (DNRF; grant 141 to ATLAS) and the INTEGRa research infrastructure funded by NNF. D.D.Z. is supported by the Melanoma Research Alliance young investigator grant (MRA 620385), C.P. is a recipient of a PhD fellowship from the Danish Cancer Research Foundation (Dansk Kraeft-forskningsfond, DKF-0-0-532), F.F. is supported by an AIRC Fellowship for Italy, and E.M. and C.M. are supported by Fondazione Umberto Veronesi. L.L. is supported by Independent Research Fund Denmark – Sapere Aude Starting Grant (8048-00072A) and the Novo Nordisk Foundation (NNF21OC0071718). CRISPR gene editing in the laboratory of Y.L. is partially supported by the European Union's Horizon 2020 research and innovation program under grant agreement 899417. Cancer Structural Biology, Redox Biology, and Melanoma Research Team labs are part of the Center of Excellence for Autophagy, Recycling and Disease (CARD), funded by Danmarks Grundforskningsfond (DNRF125). S.R. and G.F. conceived the study and designed experiments. S.R. C.P. P.G. and E.M. carried out the biochemical and microscopy experiments. S.R. and C.P. prepared samples for RNA sequencing (RNA-seq) and analyzed the data. P.G. F.F. and C.M. performed biotin switch assays. M.P. and B.B. designed and performed mass spectrometry analysis. S.R. L.D.L. and D.D.Z. designed and carried out xenograft experiments. L.D.L. performed immunohistochemistry analysis on tumor sections. F.M.B. performed the histopathological evaluation of tumor xenografts. T.S.P. L.L. and Y.L. designed and established FAK1 knockout and mutant-FAK1 cell lines by CRISPR-Cas9. E.P. and V.R. investigated GSNOR expression on TGCA database. E.P. and J.S.V. worked on FAK1 3D structure and meta-paths analysis. L.D.L. and E.M. provided critical support, key data analyses, and conceptual advice. S.R. and G.F. wrote the original draft. S.R. organized and archived unprocessed data and figures. All authors took part in reviewing and editing the final manuscript. All authors read and accepted the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

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© 2023 The Author(s)

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