Carcinoma-associated fibroblasts (CAFs) play an important role in the progression of multiple malignancies. Secretion of cytokines and growth factors underlies the pro-tumoral effect of CAFs. Although this paracrine function has been extensively documented, the molecular mechanisms controlling the expression of these factors remain elusive. In this study, we provide evidence of a novel CAF transcriptional axis regulating the expression of SDF1, a major driver of cancer cell migration, involving the transcription factor GLI1 and histone acetyltransferase p300. We demonstrate that conditioned media from CAFs overexpressing GLI1 induce the migration of pancreatic cancer cells, and this effect is impaired by an SDF1-neutralizing antibody. Using a combination of co-immunoprecipitation, proximity ligation assay and chromatin immunoprecipitation assay, we further demonstrate that GLI1 and p300 physically interact in CAFs to co-occupy and drive SDF1 promoter activity. Mapping experiments highlight the requirement of GLI1 N-terminal for the interaction with p300. Importantly, knockdowns of both GLI1 and p300 reduce SDF1 expression. Further analysis shows that knockdown of GLI1 decreases SDF1 promoter activity, p300 recruitment, and levels of its associated histone marks (H4ac, H3K27ac, and H3K14ac). Finally, we show that the integrity of two GLI binding sites in the SDF1 promoter is required for p300 recruitment. Our findings define a new role for the p300–GLI1 complex in the regulation of SDF1, providing new mechanistic insight into the molecular events controlling pancreatic cancer cells migration.
Skip Nav Destination
Article navigation
February 2023
-
Cover Image
Cover Image
The image illustrates the mechanism underlying GLI1-induced migration of pancreatic cancer cells through the induction of SDF1 in cancer-associated fibroblast. Read more from Martín Fernández-Zapico and colleagues on pages 225–241.
Research Article|
February 14 2023
GLI1 interaction with p300 modulates SDF1 expression in cancer-associated fibroblasts to promote pancreatic cancer cells migration
Renzo E. Vera;
Renzo E. Vera
Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - original draft, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
María J. Lamberti;
María J. Lamberti
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
2Instituto de Biotecnología Ambiental y Salud (INBIAS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Río Cuarto, Córdoba, Argentina
Search for other works by this author on:
Luciana L. Almada;
Luciana L. Almada
Conceptualization, Formal analysis, Investigation, Methodology, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Ezequiel J. Tolosa;
Ezequiel J. Tolosa
Conceptualization, Formal analysis, Investigation, Methodology, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Anne M. Vrabel;
Anne M. Vrabel
Formal analysis, Investigation, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Ashley N. Sigafoos;
Ashley N. Sigafoos
Investigation, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Merih D. Toruner;
Merih D. Toruner
Formal analysis, Investigation, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Luis F. Flores;
Luis F. Flores
Formal analysis, Investigation, Writing - review & editing
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Search for other works by this author on:
Viviana A. Rivarola;
Viviana A. Rivarola
Conceptualization, Investigation, Writing - review & editing
2Instituto de Biotecnología Ambiental y Salud (INBIAS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Río Cuarto, Córdoba, Argentina
Search for other works by this author on:
Natalia B. Rumie Vittar;
Natalia B. Rumie Vittar
Conceptualization, Formal analysis, Writing - review & editing
2Instituto de Biotecnología Ambiental y Salud (INBIAS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Río Cuarto, Córdoba, Argentina
Search for other works by this author on:
Martín E. Fernández-Zapico
1Schulze Center for Novel Therapeutics, Mayo Clinic, Division of Oncology Research, Rochester, MN 55905, U.S.A.
Correspondence: Martín E. Fernández-Zapico (FernandezZapico.Martin@mayo.edu)
Search for other works by this author on:
Biochem J (2023) 480 (3): 225–241.
Article history
Received:
October 17 2022
Revision Received:
February 02 2023
Accepted:
February 02 2023
Citation
Renzo E. Vera, María J. Lamberti, Luciana L. Almada, Ezequiel J. Tolosa, Anne M. Vrabel, Ashley N. Sigafoos, Merih D. Toruner, Luis F. Flores, Viviana A. Rivarola, Natalia B. Rumie Vittar, Martín E. Fernández-Zapico; GLI1 interaction with p300 modulates SDF1 expression in cancer-associated fibroblasts to promote pancreatic cancer cells migration. Biochem J 15 February 2023; 480 (3): 225–241. doi: https://doi.org/10.1042/BCJ20220521
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
441
Views