The histone acetyltransferase inhibitor CPTH6 impairs tumor angiogenesis acting on both endothelial and cancer cells

Protein acetylation is typically catalyzed by enzymes with histone acetyltransferase (HATs) or histone deacetylase (HDACs) activity. To date, it has been identified the involvement of protein acetylation in different tumorigenic signaling events, including angiogenesis. The biological process of neo-vasculature formation from pre-existing blood vessels is widely considered to be an essential process to sustain tumor growth as well as to provide a route for tumor cell metastatization. In this context, the role exerted by HDACs in tumor angiogenesis is well known, whilst the role of HATs is largely unknown. Among molecules with HAT inhibitory activity, the thiazole derivative CPTH6 has been characterized by our group for its antitumor activity in different tumor models, including non-small cell lung cancer (NSCLC). In this study, we assessed the effect of CPTH6 on angiogenesis-related properties of both endothelial and NSCLC cells. The human umbilical vein endothelial cell (HUVEC) and H1299 NSCLC cell lines were used. HUVEC and H1299 morphogenesis was analyzed by plating cells on matrigel and evaluating their ability to organize capillary-like structures. The effect of CPTH6 on protein acetylation was assessed by WB analysis. Transwell supports were employed to evaluate HUVEC migration and invasion. Human Angiogenesis Antibody Array was used to test the conditioned media derived from CPTH6-treated H1299 cells. C57/BL6 and nude mice were used to perform matrigel plug assay and to evaluate tumor growth, respectively. IHC analysis of CD31 was employed to evaluate the number of intra-tumor vessels in tumor xenografts. The HAT inhibitor CPTH6 affected some endothelial cell functions in vitro. In particular, CPTH6 impaired HUVEC invasion, migration and differentiation abilities at doses that did not alter proliferation. Although CPTH6 did not affect histone H3 acetylation, it slightly reduced α-tubulin acetylation in HUVEC. In addition, CPTH6 decreased the neovascularization in vivo, as evidenced by the impairment of the VEGF-induced vascularization of matrigel plugs. Interestingly, CPTH6 affected also the angiogenesis-related properties of cancer cells. In particular, this compound reduced the ability of H1299 to organize capillary like structures and, conditioned media derived from CPTH6-treated H1299 cells, impaired HUVEC morphogenesis. Accordingly, CPTH6 reduced the secretion of some pro-angiogenic factors (VEGF, EGF, ANG, TIE-2, TNF-α) and, at the same time, increased the release of anti-angiogenic ones (Endostatin, PLG). Finally, in H1299-tumor xenografts, CPTH6 decreased significantly the number of intra-tumor vessels, even though it did not impair tumor growth. Overall, this study adds information to the role of HATs in tumor angiogenesis, and proposes HAT inhibition as an attractive target for antiangiogenic therapy of NSCLC. Citation Format: Marta Di Martile, Marianna Desideri, Simonetta Buglioni, Carla Azzurra Amoreo, Daniela Trisciuoglio, Donatella Del Bufalo. The histone acetyltransferase inhibitor CPTH6 impairs tumor angiogenesis acting on both endothelial and cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5.