SMYD2 INHIBITION AS A NEW THERAPEUTIC STRATEGY FOR HEPATOCELLULAR CARCINOMA

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

Congreso; Reunión de Sociedades de Biociencias 2021; 2021

Introduction: The development of therapies for hepatocellular carcinoma (HCC) remains a topic of interest since the impact of available therapies on patient survival is still poor. The methyltransferase MYD2 is an epigenetic modifier frequently upregulated in tumors that has been pointed out as a potential therapeutic target. Our aim was to explore the therapeutic potential of SMYD2 pharmacological inhibition in HCC. Methods: SMYD2 expression, its correlation with clinical prognosis and transcriptional programs relevant to the disease were explored in HCC using TCGA, ICGC and GSE1542 databases. The effect of LLY507, an SMYD2 inhibitor, on HCC cells survival, cell cycle and apoptosis were assessed by standard MTT assay and flow cytometry. RNA-Seq analysis of HuH7 cells treated with LLY507 and their correlation with HCC datasets were used to characterize the underlying mechanism upon SMYD2 inhibition. Results: We observed that SMYD2 is upregulated in the tumoral vs non-tumoral tissue and correlates with a poor prognosis when highly expressed in HCC. Additionally, we found that SMYD2 expression negatively correlates with a set of genes linked to immune-related processes, apoptosis, and MAPK pathway, and that are downregulated in HCC. The pharmacological inhibition of SMYD2 by LLY507 showed a potent in vitro antitumoral effect, induced cell cycle arrest and apoptosis. Finally, RNA-seq of LLY507-treated HCC cells revealed the downregulation of aggressive, cell cycle-related genes, as well as the upregulation of immune genes that correlate negatively with SMYD2. Conclusions: The bioinformatic analysis of public HCC datasets showed that SMYD2 can be considered a new therapeutic target for HCC. The targeted inhibition of SMYD2 by LLY507 has a potent antiproliferative effect on HCC cells and reverts an oncogenic transcriptional program. These data suggest that inhibition of SMYD2 merits further investigation as a therapeutic target in HCC.