title: Acetylation of histone H3 prevents resistance development caused by chronic mTOR inhibition in renal cell carcinoma cells.
abstract: Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.
authors.affiliation: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Juengel
authors.forename: Anna
authors.initials: A
authors.lastname: Dauselt
authors.forename: Jasmina
authors.initials: J
authors.lastname: Makarević
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesner
authors.forename: Igor
authors.initials: I
authors.lastname: Tsaur
authors.forename: Georg
authors.initials: G
authors.lastname: Bartsch
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D034741:RNA, Small Interfering; D014635:Valproic Acid; D000068338:Everolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus