Histone deacetylase 10 relieves repression on the melanogenic program by maintaining the deacetylation status of repressors.
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.
Lai
I-Lu
IL
Institute of Molecular Biology, National Chung Hsing University, Taichung 40227, Taiwan.
Lin
Tung-Ping
TP
Yao
Ya-Li
YL
Lin
Ching-Yi
CY
Hsieh
Mei-Ju
MJ
Yang
Wen-Ming
WM
D002460:Cell Line; D005786:Gene Expression Regulation; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28
D050883:HSC70 Heat-Shock Proteins; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D046912:Multiprotein Complexes; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; C447828:HDAC10 protein, human; D006655:Histone Deacetylases; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase