HDAC10 belongs to the class II histone deacetylase family; however, its functions remain enigmatic. We report here that the HDAC10 protein complex contained deacetylated chaperone protein hsc70, and HDAC10 relieved repression of melanogenesis by decreasing the repressional activity of two transcriptional regulators, paired box protein 3 (Pax3) and KRAB-associated protein 1 (KAP1). HDAC10 physically interacted with Pax3 and KAP1 in a ternary complex and maintained Pax3 and KAP1 in a deacetylated state. Deacetylated Pax3 and KAP1 derepressed promoters of microphthalmia-associated transcription factor (MITF) and melanocyte-specific tyrosinase-related protein 1 and 2 (TRP-1 and TRP-2), three genes of the melanogenesis cascade, in a trichostatin A-sensitive manner. Co-occupancy of melanogenic promoters by HDAC10, Pax3, and KAP1 only happened in cells of the melanocyte lineage, and KAP1 facilitated nuclear enrichment of HDAC10. Finally, cellular melanin content correlated directly with the expression level and activity of HDAC10. Our results not only show that HDAC10 regulates melanogenesis but also demonstrate that the transcriptional activities of Pax3 and KAP1 are intimately linked to their acetylation status.It is well established that histone acetyltransferases and histone deacetylases (HDACs) 3 dynamically modify the N termini of core histones, change the chromatin structure, and modulate transcription. Histone acetyltransferases transfer acetyl groups from acetyl-CoA to the ⑀-amino group of lysine residues, thereby neutralizing the positive charge of the histone tails and decreasing their affinity for DNA. HDACs, in contrast, catalyze the hydrolysis of N-acetyllysines and restore the positive charge Previous reports demonstrated that histone acetyltransferases/HDACs modify not only core histones but also nonhistone proteins, most of which are transcription factors (for review, see 4). Acetylation/deacetylation of transcription factors may affect their DNA-binding activities, protein stability, or protein-protein interactions, thereby contributing to proper transcriptional regulation.HDAC10 is a member of the class II HDAC family (5-8). The expression level of HDAC10 decreases in patients with lung cancer (9), suggesting that HDAC10 is important for maintaining the normal behavior of cells. Although HDAC10 represses transcription when tethered to a target promoter, a fundamental understanding of the function of HDAC10 remains elusive. In this report, we show that HDAC10 interacted with nonhistone proteins and kept them in a deacetylated form. Deacetylated heat shock protein 70 was a component of the HDAC10 stable protein complex. More important, in cells of melanogenic lineage, deacetylated paired box protein 3 (Pax3) and Krüppel-associated box (KRAB)-associated protein 1 (KAP1) derepressed promoters of microphthalmia-associated transcription factor (MITF) and melanocyte-specific tyrosinase-related protein 1 and 2 (TRP-1 and TRP-2), three genes that control the melanogenesis program. HDAC10 not only formed a ter...

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