title: Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death.
abstract: Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor β receptor II (TGFβRII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGFβ signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGFβ signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGFβ/protein kinase A signaling pathway. Induction of TGFβRII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGFβRII might potentially benefit from the use of this histone deacetylase inhibitor.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Howell
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Teggart
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Aparajita
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Person
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Bowers
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696. Electronic address: mbrattain@unmc.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
mesh_terms: D002384:Catalysis; D016923:Cell Death; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides; D000077022:Survivin; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D013449:Sulfonamides; D000077022:Survivin; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C487081:belinostat