Ricerc@Sapienza

Background: Understanding 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.
Methods: The 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.
Results: CPTH6 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.
Conclusion: Overall, 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.