PO-114 Histone deacetylase 6 regulates NOTCH3 endosomal trafficking and degradation in T-cell acute lymphoblastic leukaemia cells

Abstract

IntroductionHepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signalling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor Capicua/CIC as a suppressor of HCC progression and a potential therapeutic target.Material and methodsWe used human HCC patients samples, tissue microarray, and TCGA database to check CIC levels between normal and HCC patients. We used various HCC cell lines to check cell proliferation, migration, and invasion activity by using CIC knockdown, CIC overexpression, or ETV4 knockdown cells and so on. Also we used two different mouse models, Xenograft and liver specific CIC knockout mice to evaluate tumour progression, metastasis, or survival.Results and discussionsExpression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. Levels of polyoma enhancer activator 3 (PEA3) group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETS translocation variant 4 (ETV4) is the most significantly up-regulated in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, it induces expression of matrix metalloproteinase 1 (MMP1), the MMP gene highly relevant to HCC progression, in HCC cells; and knockdown of MMP1 completely blocks the CIC deficiency–induced HCC cell proliferation and invasion.ConclusionOur study demonstrates that the CIC–ETV4–MMP1 axis is a novel regulatory module controlling HCC progression.