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

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.

Resveratrol induces DNA damage-mediated cancer cell senescence through the DLC1–DYRK1A–EGFR axis

“…Tetraspanin 5 (TSPAN5) is strongly up-regulated in DLC1-deficient HCC cells, while silencing TSPAN5 induces oncogene-induced senescence mediated by the p16/pRb pathways. 45 Depletion of the transcriptional coactivators MLK1/2 eliminates DLC1-deficient HCC xenograft growth, but reconstitution of DLC1 in HuH7 HCC cells induces cell senescence. 14 Our previous results have shown that DLC1 promotes cell senescence through the FoxO3a/NF-κB signaling pathway or endoplasmic reticulum stress after resveratrol treatment in lung and breast cancer cells.…”

LPA receptor 1 (LPAR1) is a novel interaction partner of Filamin A that promotes Filamin A phosphorylation, MRTF-A transcriptional activity and oncogene-induced senescence

“…Our previous studies demonstrated that pharmacological blockade or depletion of MRTFs or their target genes Myoferlin or Tetraspanin 5 inhibits HCC growth by inducing oncogene-induced senescence [ 3 , 8 , 10 , 11 ]. We therefore searched for novel druggable targets at the plasma membrane overexpressed in human HCC patient samples that could constitute novel therapeutic targets to prevent MRTF function and HCC growth.…”

“…Since senescence induction functions as a tumor-suppressive mechanism, strategies aimed at the induction of cellular senescence have gained considerable attention for HCC therapy [ 3 ]. We recently implicated MRTFs and their target genes Myoferlin and Tetraspanin 5 in the senescence response [ 10 , 11 ], but the mechanisms driving the MRTF-associated senescence response remain unclear. Here, we show that LPAR1 activation facilitates FLNA phosphorylation at S2152, complex formation with MRTF-A, stress fiber- and focal adhesion formation, whereas impairment of FLNA phosphorylation caused by LPAR1 depletion or blockade redistributes MRTF-A to the cytoplasm and drives HCC cells into senescence.…”

“…We found that pharmacological inhibition of MRTF-A nuclear localization by the TRPM7 inhibitor NS8593 has antitumor effects by triggering oncogene-induced senescence [ 8 ]. Targeting MRTFs and their target genes Myoferlin (MYOF) and Tetraspanin 5 (TSPAN5) results in growth arrest mediated by oncogene-induced senescence in HCC cells and xenografts [ 9 , 10 ]. Besides MYOF and TSPAN5, SM22 is aMRTF-A-dependent target gene [ 11 ] that was reported to be upregulated during gastric cancer progression and metastasis [ 12 ].…”

High Expression of Tetraspanin 5 as a Prognostic Marker of Colorectal Cancer

“…TSPAN5 has a regulatory effect on the transport of ADAM10 from vesicles to the protoplasmic reticulum, and regulatory disturbances in these interactions may be associated with disorders that cause cancer, Alzheimer’s disease, or inflammation [ 18 , 19 ]. In cancerous tumors, TSPAN5 plays a role in hepatocellular carcinoma (HCC) metastasis through epithelial-mesenchymal transition [ 20 ] and regulates the growth of HCC in co-operation with other genes [ 21 ]. However, its role in colorectal cancer has not been clearly identified.…”