Sumoylation pathway is required to maintain the basal breast cancer subtype.
The TFAP2C/AP-2γ transcription factor regulates luminal breast cancer genes, and loss of TFAP2C induces epithelial-mesenchymal transition. By contrast, the highly homologous family member, TFAP2A, lacks transcriptional activity at luminal gene promoters. A detailed structure-function analysis identified that sumoylation of TFAP2A blocks its ability to induce the expression of luminal genes. Disruption of the sumoylation pathway by knockdown of sumoylation enzymes, mutation of the SUMO-target lysine of TFAP2A, or treatment with sumoylation inhibitors induced a basal-to-luminal transition, which was dependent on TFAP2A. Sumoylation inhibitors cleared the CD44(+/hi)/CD24(-/low) cell population characterizing basal cancers and inhibited tumor outgrowth of basal cancer xenografts. These findings establish a critical role for sumoylation in regulating the transcriptional mechanisms that maintain the basal cancer phenotype.
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Maria V
MV
Bogachek
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Yizhen
Y
Chen
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Mikhail V
MV
Kulak
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
George W
GW
Woodfield
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Anthony R
AR
Cyr
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
Jung M
JM
Park
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Philip M
PM
Spanheimer
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Yingyue
Y
Li
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA; The Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
Tiandao
T
Li
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA; Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA. Electronic address: ronald-weigel@uiowa.edu.
Ronald J
RJ
Weigel
D000818:Animals; D001943:Breast Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D005810:Multigene Family; D018295:Neoplasms, Basal Cell / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D025841:Small Ubiquitin-Related Modifier Proteins; C493673:TFAP2A protein, human; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2