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Histone deacetylases (HDACs) are a group of enzymes that deacetylate ε-N-acetyl lysine residues of histone and non-histone proteins and play an important role in gene regulation. HDAC4, a class-IIa HDAC, has been reported to shuttle between nucleus and cytoplasm in response to various cellular stimuli. The nucleo-cytoplasmic shuttling of HDAC4 is critical, and an anomalous nuclear localization might affect the cellular differentiation program. While the subcellular localization of HDAC4 has been reported to be vital for myoblast differentiation and chondrocyte hypertrophy, nuclear accumulation of HDAC4 during Runx2-induced osteoblast differentiation of stem cells has not been characterized. Ratjadone C is a natural compound that inhibits the nuclear export of proteins. Here, we show that Runx2 is a more potent transcription factor than Osterix in inducing osteoblast differentiation. Under the influence of ratjadone C, HDAC4 is retained in the nucleus and co-localizes with Runx2. However, forced nuclear accumulation of HDAC4 by ratjadone C or overexpression of the nuclear resident form of HDAC4 does not inhibit osteoblast differentiation, suggesting that the Runx2- induced osteogenic program of C3H10T1/2 cells is not affected by HDAC4. Even though phosphorylation of HDAC4 affects its compartmentalization and the stemness of progenitor cells, we found that total HDAC4 and phosphorylated HDAC4 remain cytoplasmic under both osteogenic and nonosteogenic conditions. Collectively, this work demonstrates that, regardless of the nucleo-cytoplasmic presence of HDAC4, the Runx2-induced osteoblast differentiation program of C3H10T1/2 cells remains unaffected. Additionally, the ratjadone C-mediated nuclear retention assay can potentially be used as a screening tool to identify novel regulatory mechanisms of HDAC4 and its functional partners in various pathophysiological conditions.

Ratjadone C-Mediated Nuclear Accumulation of HDAC4: Implications on Runx2-Induced Osteoblast Differentiation of C3H10T1/2 Mesenchymal Stem Cells