A role for paralog-specific sumoylation in histone deacetylase 1 stability.
Histone deacetylase 1 (HDAC1) is an essential epigenetic regulator belonging to a highly conserved family of deacetylases. Increased HDAC1 activity and expression often correlates with neoplastic transformation. Here we show how specific modification of HDAC1 by SUMO1, but not by SUMO2, facilitates HDAC1 degradation. Our findings reveal that SUMO1, but not SUMO2, conjugation to HDAC1 promotes HDAC1 ubiquitination and degradation. This is suggested by the observation that in non-tumorigenic mammary epithelial cells HDAC1 is preferentially conjugated to SUMO1 leading to HDAC1 proteolysis, whereas in breast cancer cells HDAC1 is more conjugated to SUMO2, promoting HDAC1 protein stability. SUMO E3 ligases play an important role in paralog-specific conjugation; in particular, the SUMO E3 ligase PIASy, which is overexpressed in breast cancer cells, selectively promotes the conjugation of HDAC1 to SUMO2. Therefore, cell environment affects paralog-specific sumoylation of HDAC1, whose conjugation to SUMO1 but not to SUMO2 facilitates its protein turnover. Our findings uncover a role for paralog-specific sumoylation of HDAC1 whose significance is emphasized by the use of HDAC inhibitors as anticancer drugs.
Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, 20139 Milan, Italy.
Simona
S
Citro
Ellis
E
Jaffray
Ronald T
RT
Hay
Christian
C
Seiser
Susanna
S
Chiocca
D015153:Blotting, Western; D045744:Cell Line, Tumor; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D055550:Protein Stability; D025842:SUMO-1 Protein / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination
D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
HDAC1; PIAS; SUMO; breast cancer; ubiquitin