SMYD2 as a new therapeutic target for hepatocellular carcinoma.

BUELONI B ; CANTERO MJ; DOMINGUEZ L; ATORRASAGASTI C; GARCIA M; FIORE E; BAYO FINA JM; MAZZOLINI G

Congreso; Reunión Conjunta SAIC SAI&FAIC SAFIS 2022; 2022

Introduction: Available therapies for hepatocellular carcinoma (HCC) have a modest impact on patient survival, making it necessary to develop new treatments. SMYD2 is a methyltransferase that acts as an oncogene in numerous types of cancers. The aim of our work is to assess the therapeutic potential of SMYD2 pharmacological inhibition in HCC. Methods: SMYD2 expression levels and correlated relevant pathways were explored using public HCC datasets. HCC cells survival, cell cycle and apoptosis following treatment with SMYD2 inhibitors (AZ505 and LLY507) were assessed by standard MTT assay and flow cytometry. Mechanistic study was performedwith RNA-seq analysis of HuH7 cells treated with LLY507. In vivo therapeutic potential of SMYD2 inhibitors was evaluated on an orthotopic HCC model in C3H/HeN mice. Results: SMYD2 is significantly upregulated in tumoral tissue from patients with HCC. We further found a negative correlation between SMYD2 expression and immune-related genes and apoptotic processes that are downregulated in HCC. SMYD2 inhibition by LLY507 induces cell cycle arrest and apoptosis on HCC cells. RNA-seq of LLY507-treated HCC cells revealed that there is a downregulation of aggressive and cell cycle-related genes. Most importantly, LL507 and AZ505 strongly inhibits tumor growth in vivo. Conclusions: Public human HCC datasets bioinformatic analysis shows that SMYD2 can be considered a novel therapeutic target for HCC. Targeted inhibition of SMYD2 exerts a potent antitumoral effect both in vitro and in vivo and reverts oncogenic transcriptional programs.