Filamin a binds deleted in liver cancer 1 (DLC1) to promote its tumor suppressor activity and inhibit the SRF coactivator MRTF-A

Sergeev M, Meier M, Wohlleben P, Rupprecht L, Kupraszewicz-Hutzler M, Hilgers KF, Hartner A, Vögele AL, Atreya R, Frey Y, Srirangan S, Eichler J, Confais C, Hédan B, Jarry U, Olayioye MA, Mühlich S (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Neoplasia Neoplasia

Book Volume: 71

Article Number: 101258

DOI: 10.1016/j.neo.2025.101258

Abstract

Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) in vitro and in vivo in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.

Authors with CRIS profile

Michael Sergeev Professur für Molekulare und Klinische Pharmazie Melanie Meier Professur für Molekulare und Klinische Pharmazie Petra Wohlleben Professur für Molekulare und Klinische Pharmazie Laura Rupprecht Professur für Molekulare und Klinische Pharmazie Karl Friedrich Hilgers Professur für Innere Medizin (Hochdruckforschung) Andrea Hartner Department of Paediatrics and Adolescent Medicine Anna-Lena Vögele Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Showmika Srirangan Professur für Pharmazeutische Chemie Jutta Eichler Professur für Pharmazeutische Chemie Susanne Mühlich Professur für Molekulare und Klinische Pharmazie

Involved external institutions

Universität Stuttgart DE Germany (DE) Institut de Génétique & Développement de Rennes (IGDR) FR France (FR) Biotrial FR France (FR)

How to cite

APA:

Sergeev, M., Meier, M., Wohlleben, P., Rupprecht, L., Kupraszewicz-Hutzler, M., Hilgers, K.F.,... Mühlich, S. (2026). Filamin a binds deleted in liver cancer 1 (DLC1) to promote its tumor suppressor activity and inhibit the SRF coactivator MRTF-A. Neoplasia, 71. https://doi.org/10.1016/j.neo.2025.101258

MLA:

Sergeev, Michael, et al. "Filamin a binds deleted in liver cancer 1 (DLC1) to promote its tumor suppressor activity and inhibit the SRF coactivator MRTF-A." Neoplasia 71 (2026).

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