SMYD2 AS A NEW THERAPEUTIC TARGET FOR HEPATOCELLULAR CARCINOMA

BARBARA BUELONI; CANTERO, MARIA JOSE; DOMÍNGUEZ, LUCIANA; ATORRASAGASTI, CATALINA; GARCÍA, MARIANA; ESTEBAN FIORE; BAYO, JUAN; GUILLERMO MAZZOLINI

Congreso; LXVII Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas; 2022

Introduction: Available therapies for hepatocellular carcinoma (HCC)have a modest impact on patient survival, making it necessary todevelop new treatments. SMYD2 is a methyltransferase that actsas an oncogene in numerous types of cancers. The aim of our workis to assess the therapeutic potential of SMYD2 pharmacologicalinhibition in HCC. Methods: SMYD2 expression levels and correlatedrelevant pathways were explored using public HCC datasets.HCC cells survival, cell cycle and apoptosis following treatment withSMYD2 inhibitors (AZ505 and LLY507) were assessed by standardMTT assay and flow cytometry. Mechanistic study was performedwith RNA-seq analysis of HuH7 cells treated with LLY507. In vivotherapeutic potential of SMYD2 inhibitors was evaluated on an orthotopicHCC model in C3H/HeN mice. Results: SMYD2 is significantlyupregulated in tumoral tissue from patients with HCC. We furtherfound a negative correlation between SMYD2 expression andimmune-related genes and apoptotic processes that are downregulatedin HCC. SMYD2 inhibition by LLY507 induces cell cycle arrestand apoptosis on HCC cells. RNA-seq of LLY507-treated HCCcells revealed that there is a downregulation of aggressive and cellcycle-related genes. Most importantly, LL507 and AZ505 stronglyinhibits tumor growth in vivo. Conclusions: Public human HCC datasetsbioinformatic analysis shows that SMYD2 can be considereda novel therapeutic target for HCC. Targeted inhibition of SMYD2exerts a potent antitumoral effect both in vitro and in vivo and revertsoncogenic transcriptional programs.