STANDARD_NAME XU_RESPONSE_TO_TRETINOIN_DN SYSTEMATIC_NAME M12964 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/XU_RESPONSE_TO_TRETINOIN_DN NAMESPACE HUMAN_SEQ_ACCESSION DESCRIPTION_BRIEF Genes down-regulated in NB4 cells (acute promyelocytic leukemia, APL) by tretinoin [PubChem=444795] alone. DESCRIPTION_FULL Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which dramatically responds to all-trans-retinoic acid (ATRA). Recent studies have indicated that combinatorial use of retinoid and nonretinoid compounds, such as histone deacetylase inhibitors, arsenics, and PKA agonists, has higher therapeutic value in this disease and potentially in other malignancies. In a screen of 370 compounds, we identified benzodithiophene analogues as potent enhancers of ATRA-induced APL cell differentiation. These effects were not associated with changes in global histone acetylation and, for the most potent compounds, were exerted at very low nanomolar concentrations, and were paralleled by enhancement of some, but not all, ATRA-modulated gene expressions. Investigating the mechanism underlying the effects of these drugs on ATRA-induced APL cell differentiation, we have shown that benzodithiophenes enhance ATRA-mediated dissociation and association of corepressor N-CoR and coactivator p300 acetyltransferase, respectively, with retinoic acid receptor (RAR) alpha proteins. These data suggest that benzodithiophenes act at the level of receptor activation, possibly by affecting posttranslational modification of the receptor (and/or coregulators), thus leading to an enhancement in ATRA-mediated effects on gene expression and APL cell differentiation. Given the specificities of these low benzodithiophene concentrations for PML-RARalpha and RARalpha, these drugs may be useful for combinatorial differentiation therapy of APL and possibly other acute myelogenous leukemia subtypes in which the overall ATRA signaling is suppressed. PMID 16140955 GEOID AUTHORS Xu K,Guidez F,Glasow A,Chung D,Petrie K,Stegmaier K,Wang KK,Zhang J,Jing Y,Zelent A,Waxman S CONTRIBUTOR Kevin Vogelsang CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 2C FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS AA911231,AI302106,AV703465,BC001388,BC002827,D30658,NM_001630,NM_003550,NM_006117,NM_014226,U69127,U79718,U84404 GENE_SYMBOLS PPP3CA,RAP2A,,ANXA2,TPM4,GARS1,ANXA8L1,MAD1L1,ECI2,MOK,FUBP3,NTHL1,UBE3A FOUNDER_NAMES