Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activity.
SDS3 is a key component of the histone deacetylase (HDAC)-dependent Sin3A co-repressor complex, serving to maintain its HDAC activity. Here, we report both exogenous and endogenous functional interaction between deubiquitinating enzyme USP17 and human SDS3 by MALDI-TOF-MS, co-immunoprecipitation assay, and GST pull-down assay. In this study, we demonstrated that SDS3 readily undergoes endogenous polyubiquitination, which is associated specifically with Lys-63-branched polyubiquitin chains and not with Lys-48-branched polyubiquitin chains. Further, we also demonstrated that USP17 specifically deubiquitinates Lys-63-linked ubiquitin chains from SDS3 and regulates its biological functions. The deubiquitinating activity of USP17 on SDS3 negatively regulates SDS3-associated HDAC activity. The constitutive expression of USP17 and its substrate SDS3 was involved in the inhibition of anchorage-independent tumor growth and blocks cell proliferation, leading to apoptosis in cervical carcinoma cells. Furthermore, we showed that USP17 and SDS3 mutually interact with each other to regulate cancer cell viability. These data support the possibility that SDS3, being a substrate of USP17, may play an important role in developing a novel therapeutic means to inhibit specific HDAC activities in cancer.
Department of Biomedical Science, CHA University, CHA General Hospital, Seoul 135-081, Korea.
Suresh
S
Ramakrishna
Bharathi
B
Suresh
Eung-Ji
EJ
Lee
Hey-Jin
HJ
Lee
Woong-Shick
WS
Ahn
Kwang-Hyun
KH
Baek
D002470:Cell Survival; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D054875:Ubiquitination / Q000502:physiology*
D009363:Neoplasm Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D010450:Endopeptidases; C484854:USP17L2 protein, human; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D008239:Lysine
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