Endothelial progenitor cells contribute to neovascularization of non‐small cell lung cancer via histone deacetylase 7‐mediated cytoskeleton regulation and angiogenic genes transcription

To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) home to tumor sites and contribute to neovascularization. Although the precise mechanism of EPCs‐induced neovascularization remains poorly understood in non‐small cell lung cancer (NSCLC), histone deacetylase 7 (HDAC7) is considered as a critical regulator. To explore the function of HDAC7 in neovascularization induced by EPCs, tube formation assay, immunofluorescence, microarray, Western blot analysis and animal models were performed. In vitro, HDAC7 abrogation led to the activation of Rho‐associated coiled‐coil containing protein kinase/myosin light chain 2 pathway concomitant with ERK dephosphorylation, causing the instability of cytoskeleton and collapse of tube formation. In vivo, absence of HDAC7 impaired the vascular lumen integrity and decreased the functional blood perfusion, inhibiting the growth of tumor. At the level of transcription, HDAC7 silencing upregulated antiangiogenic genes and suppressed proangiogenic genes collectively, turning off the angiogenic switch during vessel formation. Taken together, HDAC7 plays a dual role in maintaining the structural and nonstructural functions of EPCs. Our work demonstrates the molecular mechanism by which HDAC7 contributes to the angiogenic property of EPCs and provides a rational basis for specific targeting of antiangiogenic strategies in lung cancer. What's new? Endothelial progenitor cells (EPCs) are highly proliferative and facilitate new blood vessel formation in cancer. Circulating EPC number is elevated in non‐small cell lung cancer (NSCLC) and is correlated with survival. Whether EPCs are also associated with angiogenesis in NSCLC remains unclear. In this study, an increased number of EPCs circulating in peripheral blood was correlated with NSCLC stage. Deletion of histone deacetylase 7 (HDAC7) in EPCs impaired functional vessel formation, repressing neovascularization for tumor progression via transcriptional modulation of pro‐ and anti‐angiogenic genes. The results suggest that HDAC7 is a promising target for EPC‐based anti‐angiogenic therapy.