Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence

dc.contributor.authorSchreyer, Laura
dc.contributor.authorMittermeier, Constanze
dc.contributor.authorFranz, Miriam J.
dc.contributor.authorMeier, Melanie A.
dc.contributor.authorMartin, Dietmar E.
dc.contributor.authorMaier, Kerstin C.
dc.contributor.authorHuebner, Kerstin
dc.contributor.authorSchneider-Stock, Regine
dc.contributor.authorSinger, Stephan
dc.contributor.authorHolzer, Kerstin
dc.contributor.authorFischer, Dagmar
dc.contributor.authorRibback, Silvia
dc.contributor.authorLiebl, Bernhard
dc.contributor.authorGudermann, Thomas
dc.contributor.authorAigner, Achim
dc.contributor.authorMuehlich, Susanne
dc.date.accessioned2021-11-09
dc.date.available2023-10-11T12:39:06Z
dc.date.created2021
dc.date.issued2021-11-09
dc.description.abstractSimple Summary Hepatocellular carcinoma (HCC) ranks second among the leading causes of cancer-related death. Since current therapeutic options are very limited, a deeper understanding of the molecular mechanisms underlying the tumor onset and progression of HCC holds great potential for improved therapeutic options. Although it has been shown that deleted in liver cancer 1 (DLC1) acts as a tumor suppressor whose allele is lost in 50% of liver cancers, alterations in gene expression initiated by DLC1 loss have not yet been the primary focus of liver cancer research. To identify novel gene targets that allow for a personalized medicine approach for HCC therapy, we performed gene expression profiling for HepG2 cells stably expressing DLC1shRNA. We provide evidence that TSPAN5 is required for HCC growth, migration and invasion, and dissected the underlying molecular mechanisms involving myocardin-related transcription factors. Thus, TSPAN5 represents a novel therapeutic target for the treatment of HCC characterized by DLC1 loss. 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.en
dc.identifier.citationCancers 13.21 (2021): 5373. <https://www.mdpi.com/2072-6694/13/21/5373>
dc.identifier.doihttps://doi.org/10.3390/cancers13215373
dc.identifier.issn2072-6694
dc.identifier.opus-id17482
dc.identifier.urihttps://open.fau.de/handle/openfau/17482
dc.identifier.urnurn:nbn:de:bvb:29-opus4-174827
dc.language.isoen
dc.publisherMDPI
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.de
dc.subjectDLC1
dc.subjectTSPAN5
dc.subjectMKL1
dc.subjectMRTF
dc.subjectSRF
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleTetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescenceen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.date.prevpublished2021-10-26
local.document.articlenumber5373
local.journal.issue21
local.journal.titleCancers
local.journal.volume13
local.sendToDnbfree*
local.subject.fakultaetNaturwissenschaftliche Fakultät
local.subject.importimport
local.subject.sammlungUniversität Erlangen-Nürnberg / Eingespielte Open Access Artikel / Eingespielte Open Access Artikel 2021
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