Inhibition of lysine acetyltransferases impairs tumor angiogenesis acting on both endothelial and tumor cells

Marta Di Martile,Daniela Secci,Simonetta Buglioni,Chiara Gabellini,Cristiana Ercolani,Marta Matraxia,Daniela Trisciuoglio,Simone Carradori,Elisabetta Valentini,Donatella Del Bufalo,Valentina Farini,Massimiliano Andreazzoli,Marianna Desideri

doi:10.1186/s13046-020-01604-z

Abstract

BackgroundUnderstanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells.MethodsThe in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6.ResultsCPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells.ConclusionOverall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.

Highlights

Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research
Even if some anti-angiogenic agents are already tested in clinical trials [3, 4], current experimental data suggest that there are several adaptive mechanisms facilitating the resistance to these therapies [2, 3], including vasculogenic mimicry (VM), an alternative process that involves tumor vascularization primed by tumor cells [5]
CPTH6 impairs in vivo and in vitro angiogenesis In order to study the possible effect on angiogenesis of CPTH6, a thiazole derivative inducing histone acetyltransferase (HAT) inhibition [17, 19], we performed matrigel plug angiogenesis assay in mice

Summary

Introduction

Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. We assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells. While the HDACs can affect endothelial angiogenic functions by controlling specific genes/pathways involved in different phases of angiogenesis [10,11,12,13,14], the function of HATs in ECs biology and blood vessel development remains entirely unexplored. In order to explore the hypothesis that HATs may provide key therapeutic targets for manipulation of angiogenic responses and new clues for anti-angiogenesis therapies, we investigated the effect of the HAT inhibitor 3-methylcyclopentylidene[4-(4′-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6) [17,18,19] on both ECs and cancer cells by using in vitro and in vivo functional assays

Methods

Results

Conclusion