title: 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.affiliation: Department of Pediatrics, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Riolo
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Michael P
authors.initials: MP
authors.lastname: Holloway
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Evgeny
authors.initials: E
authors.lastname: Yakirevich
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Altura
mesh_terms: D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism; D008239:Lysine; D051379:Mice; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D000077022:Survivin; D000097606:Exportin 1 Protein
chemical_list: D050882:CREB-Binding Protein; D004967:Estrogens; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D008239:Lysine; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000077022:Survivin; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C433811:HDAC6 protein, human