Tetraspanin 5 (Tspan5), a novel gatekeeper of the tumor suppressor dlc1 and myocardin-related transcription factors (mrtfs), controls hcc growth and senescence

Schreyer L, Mittermeier C, Franz M, Meier M, Martin DE, Maier KC, Hübner K, Schneider-Stock R, Singer S, Holzer K, Fischer D, Ribback S, Liebl B, Gudermann T, Aigner A, Mühlich S (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cancers MDPI

Book Volume: 13

Article Number: 5373

Journal Issue: 21

DOI: 10.3390/cancers13215373

Abstract

Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPase-activating protein (RhoGAP) which accelerates the return of RhoGTPases to an inactive state. We recently described that the restoration of DLC1 expression induces cellular senescence. However, this principle is not amenable to direct therapeutic targeting. We therefore performed gene expression profiling for HepG2 cells depleted of DLC1 to identify druggable gene targets mediating the effects of DLC1 on senescence induction. This approach revealed that versican (VCAN), tetraspanin 5 (TSPAN5) and N-cadherin (CDH2) were strongly upregulated upon DLC1 depletion in HCC cells, but only TSPAN5 affected the proliferation of HCC cells and human HCC. The depletion of TSPAN5 induced oncogene-induced senescence (OIS), mediated by the p16INK4a/pRb pathways. Mechanistically, silencing TSPAN5 reduced actin polymerization and thereby myocardin-related transcription factor A-filamin A (MRTF-A-FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction in vitro and in vivo. Our results identify TSPAN5 as a novel druggable target for HCC.

Authors with CRIS profile

Laura Schreyer Professur für Molekulare und Klinische Pharmazie Miriam Franz Professur für Molekulare und Klinische Pharmazie Melanie Meier Professur für Molekulare und Klinische Pharmazie Kerstin Hübner Institute of Pathology Regine Schneider-Stock Professur für Experimentelle Tumorpathologie Dagmar Fischer Lehrstuhl für Pharmazeutische Technologie und Biopharmazie Susanne Mühlich Professur für Molekulare und Klinische Pharmazie

Involved external institutions

National University of Singapore (NUS) SG Singapore (SG) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Universität Greifswald DE Germany (DE) Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit (LGL) DE Germany (DE) Universität Leipzig DE Germany (DE)

How to cite

APA:

Schreyer, L., Mittermeier, C., Franz, M., Meier, M., Martin, D.E., Maier, K.C.,... Mühlich, S. (2021). Tetraspanin 5 (Tspan5), a novel gatekeeper of the tumor suppressor dlc1 and myocardin-related transcription factors (mrtfs), controls hcc growth and senescence. Cancers, 13(21). https://dx.doi.org/10.3390/cancers13215373

MLA:

Schreyer, Laura, et al. "Tetraspanin 5 (Tspan5), a novel gatekeeper of the tumor suppressor dlc1 and myocardin-related transcription factors (mrtfs), controls hcc growth and senescence." Cancers 13.21 (2021).

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