title: MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors.
abstract: Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested in current clinical trials, the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood. To gain insight into pathways that limit HDACi efficacy in gastric cancer, we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid (SAHA). We report that higher expression levels of the anti-apoptotic BCL2 family members MCL1 and BCL(XL) were detectable in cells with high inhibitory concentration 50 (IC(50)) values for SAHA. Using RNAi, we show that MCL1 and BCL(XL) lower the efficacy of SAHA. To find strategies to interfere with MCL1 and BCL(XL) expression, we investigated molecular regulation of both proteins. We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced MCL1 and BCL(XL) expression. Subsequently, we observed an increase in SAHA efficacy. Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors. Whereas c-MYC controls transcription of MCL1 directly, regulation of BCL(XL) was due to c-MYC's capability to regulate the eIF4E gene, which encodes a rate-limiting factor of eukaryotic translation. Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer.
authors.affiliation: II Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: Wajana L
authors.initials: WL
authors.lastname: Labisso
authors.forename: Matthias
authors.initials: M
authors.lastname: Wirth
authors.forename: Natasa
authors.initials: N
authors.lastname: Stojanovic
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stauber
authors.forename: Angelika
authors.initials: A
authors.lastname: Schnieke
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D000077337:Vorinostat; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D000077337:Vorinostat; D006655:Histone Deacetylases