Runt-related transcription factor 2 (Runx2) transactivates many genes required for osteoblast differentiation. The role of N-a-acetyltransferase 10 (NAA10, arrest-defective-1), originally identified in yeast, remains poorly understood in mammals. Here we report a new NAA10 function in Runx2-mediated osteogenesis. Runx2 stabilizes NAA10 in osteoblasts during BMP-2-induced differentiation, and NAA10 in turn controls this differentiation by inhibiting Runx2. NAA10 delays bone healing in a rat calvarial defect model and bone development in neonatal mice. Mechanistically, NAA10 acetylates Runx2 at Lys225, and this acetylation inhibits Runx2-driven transcription by interfering with CBFb binding to Runx2. Our study suggests that NAA10 acts as a guard ensuring balanced osteogenesis by fine-tuning Runx2 signalling in a feedback manner. NAA10 inhibition could be considered a potential strategy for facilitating bone formation.

Abstract. HIF-1· is believed to promote tumor growth and metastasis, and many efforts have been made to develop new anticancer agents based on HIF-1· inhibition. YC-1 is a widely used HIF-1· inhibitor both in vitro and in vivo, and is being developed as a novel class of anticancer drug. However, little is known about the mechanism by which YC-1 degrades HIF-1·. As the first step for understanding the mechanism of action of YC-1, we here identified the HIF-1· domain responsible for YC-1-induced protein degradation. YC-1 blocked the HIF-1· induction by hypoxia, iron chelation, and proteasomal inhibition and also degraded ectopically expressed HIF-1·. In deletion analyses, C-terminal HIF-1· was found to be sensitively degraded by YC-1. Using a GFP-fusion method, the YC-1-induced degradation domain was identified as the aa. 720-780 region of HIF-1·. We next tested the possible involvement of HDAC7 or OS-9 in YC-1-induced HIF-1· degradation. However, their binding to HIF-1· was not affected by YC-1, suggesting that they are not involved in the YC-1 action. It is also suggested that YC-1 targets a novel pathway regulating HIF-1· stability.

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