title: Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer.
abstract: Treatment of ErbB2-overexpressing BT474 and MDA-MB-453 breast cancer cells with 1 to 10 μmol/L betulinic acid inhibited cell growth, induced apoptosis, downregulated specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and decreased expression of ErbB2. Individual or combined knockdown of Sp1, Sp3, Sp4 by RNA interference also decreased expression of ErbB2 and this response was because of repression of YY1, an Sp-regulated gene. Betulinic acid-dependent repression of Sp1, Sp3, Sp4, and Sp-regulated genes was due, in part, to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a), which constitutively inhibits ZBTB10 expression, and we show for the first time that the effects of betulinic acid on the miR-27a:ZBTB10-Sp transcription factor axis were cannabinoid 1 (CB1) and CB2 receptor-dependent, thus identifying a new cellular target for this anticancer agent.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Liu
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.forename: Ping
authors.initials: P
authors.lastname: Lei
authors.forename: KyoungHyun
authors.initials: K
authors.lastname: Kim
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Brents
authors.forename: Paul L
authors.initials: PL
authors.lastname: Prather
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D053978:Pentacyclic Triterpenes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors*; D000094062:Betulinic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D035683:MicroRNAs; D053978:Pentacyclic Triterpenes; D018719:Erb-b2 Receptor Tyrosine Kinases; D043882:Receptors, Cannabinoid; D012097:Repressor Proteins; D051703:Sp Transcription Factors; D014315:Triterpenes; D050986:YY1 Transcription Factor; D000094062:Betulinic Acid; C531388:MIRN27 microRNA, human; C559929:ZBTB10 protein, human