SMYD2 AS A NEW THERAPEUTIC TARGET FOR HEPATOCELLULAR CARCINOMA

BUELONI, BARBARA; CANTERO, MARIA JOSE; LAMEROLI, LUCÍA; ATORRASAGASTI, CATALINA; GARCIA, MARINA; FIORE, ESTEBAN; BAYO, JUAN; MAZZOLINI, GUILLERMO

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

have limited survival impact, driving the need for novel treatments.The methyltransferase SMYD2 is a potential therapeutic targetdue to its role in transcriptional regulation and its non-epigeneticsubstrates, such as the tumor suppressor p53 and the oncogenictranscription factor β-catenin. In this line, Wnt/β-catenin pathway isfrequently overactivated in immunologically unresponsive tumors.Our aim was to explore whether the pharmacological inhibition ofSMYD2 in HCC could trigger an antitumoral effect while also reducingthe immunosuppressive nature of “cold” tumors. Methods:SMYD2 expression levels and correlated relevant pathways wereexplored using public HCC datasets. SMYD2 inhibitors (AZ505 andLLY507) impact on HCC cells survival, cell cycle and apoptosiswas assessed by MTT assay and flow cytometry. RNA-seq analysiswas performed on LLY507—treated HuH7 cells. The PM299Lcell line bearing hyperactive β-catenin was used to study the effectof SMYD2 inhibition on Wnt pathway activation. In vivo effectof SMYD2 inhibitors was evaluated on an orthotopic HCC murinemodel. Genes expression was assessed by qPCR. Results: SMYD2is upregulated in HCC tumors and negatively correlates with immune-related genes and apoptotic processes that are downregulatedin HCC. LLY507 induces cell cycle arrest and apoptosis on HCCcells, and downregulates aggressive and cell cycle-related genesas revealed by RNA-seq. On J774 macrophages, SMYD2 inhibitioninduces the expression of IL-1β but reduces TGFβ production. Next,we confirmed the upregulation of β-catenin targets in PM299L cells,as well as its downregulation after AZ505 treatment. Notably, LL507and AZ505 strongly inhibit tumor growth in vivo. Tumors treatedwith AZ505 exhibit an upregulation of inflammatory genes, as well asa decrease in the expression of immunosuppressive cytokines.Principiodel formulario. Conclusions: Our results indicate that SMYD2inhibition is a potential therapeutic strategy for HCC that reverts oncogenicand immunosuppressive transcriptional programs.