title: Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation.
abstract: While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Frumm
authors.forename: Zi Peng
authors.initials: ZP
authors.lastname: Fan
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Supriya
authors.initials: S
authors.lastname: Gupta
authors.forename: Lynn
authors.initials: L
authors.lastname: VerPlank
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Suh
authors.forename: Edward
authors.initials: E
authors.lastname: Holson
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: William B
authors.initials: WB
authors.lastname: Smith
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Paranal
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bassil
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Roti
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Nicola
authors.initials: N
authors.lastname: Tolliday
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014212:Tretinoin / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D014212:Tretinoin; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2