Histone deacetylase 6 (HDAC6) deacetylates survivin for its nuclear export in breast cancer.

Abstract

Survivin is an oncogenic protein that is highly expressed in breast cancer and has a dual function that is dependent on its subcellular localization. In the cytosol, survivin blocks programmed cell death by inactivating caspase proteins; however, in the nucleus it facilitates cell division by regulating chromosomal movement and cytokinesis. In prior work, we showed that survivin is acetylated by CREB-binding protein (CBP), which restricts its localization to the nuclear compartment and thereby inhibits its anti-apoptotic function. Here, we identify histone deacetylase 6 (HDAC6) as responsible for abrogating CBP-mediated survivin acetylation in the estrogen receptor (ER)-positive breast cancer cell line, MCF-7. HDAC6 directly binds survivin, an interaction that is enhanced by CBP. In quiescent breast cancer cells in culture and in malignant tissue sections from ER+ breast tumors, HDAC6 localizes to a perinuclear region of the cell, undergoing transport to the nucleus following CBP activation where it then deacetylates survivin. Genetically modified mouse embryonic fibroblasts that lack mhdac6 localize survivin predominantly to the nuclear compartment, whereas wild-type mouse embryonic fibroblasts localize survivin to distinct cytoplasmic structures. Together, these data imply that HDAC6 deacetylates survivin to regulate its nuclear export, a feature that may provide a novel target for patients with ER+ breast cancer.

• Authors: Matthew T Riolo, Zachary A Cooper, Michael P Holloway, Yan Cheng, Cesario Bianchi, Evgeny Yakirevich, Li Ma, Y Eugene Chin, Rachel A Altura
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 14 Pg. 10885-93 (Mar 30 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22334690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BIRC5 protein, human
• Birc5 protein, mouse
• Estrogens
• Inhibitor of Apoptosis Proteins
• Karyopherins
• Receptors, Cytoplasmic and Nuclear
• Repressor Proteins
• Survivin
• CREB-Binding Protein
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases
• Lysine

Topics

• Acetylation
• Active Transport, Cell Nucleus
• Animals
• Breast Neoplasms (pathology)
• CREB-Binding Protein (metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Estrogens (metabolism)
• Histone Deacetylase 6
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Inhibitor of Apoptosis Proteins (chemistry, metabolism)
• Intracellular Space (metabolism)
• Karyopherins (metabolism)
• Lysine
• Mice
• Protein Structure, Tertiary
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Repressor Proteins (chemistry, metabolism)
• Survivin
• Exportin 1 Protein