AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer.

Autor: Beck AC; Department of Surgery, University of Iowa, Iowa City, Iowa., Cho E; Department of Surgery, University of Iowa, Iowa City, Iowa., White JR; Department of Surgery, University of Iowa, Iowa City, Iowa., Paemka L; Department of Surgery, University of Iowa, Iowa City, Iowa.; Department of Biochemistry, Cell and Molecular Biology, West African Center for Cell Biology of Infectious Pathogens, School of Biological Sciences, College of Basic and Applied Science University of Ghana, Accra, Ghana., Li T; Department of Surgery, University of Iowa, Iowa City, Iowa., Gu VW; Department of Surgery, University of Iowa, Iowa City, Iowa., Thompson DT; Department of Surgery, University of Iowa, Iowa City, Iowa., Koch KE; Department of Surgery, University of Iowa, Iowa City, Iowa., Franke C; Department of Surgery, University of Iowa, Iowa City, Iowa., Gosse M; Department of Pathology, University of Iowa, Iowa City, Iowa., Wu VT; Department of Surgery, University of Iowa, Iowa City, Iowa., Landers SR; Department of Surgery, University of Iowa, Iowa City, Iowa., Pamatmat AJ; Department of Surgery, University of Iowa, Iowa City, Iowa., Kulak MV; Department of Surgery, University of Iowa, Iowa City, Iowa., Weigel RJ; Department of Surgery, University of Iowa, Iowa City, Iowa. ronald-weigel@uiowa.edu.
Jazyk: angličtina
Zdroj: Molecular cancer research : MCR [Mol Cancer Res] 2021 Jul; Vol. 19 (7), pp. 1156-1167. Date of Electronic Publication: 2021 Mar 22.
DOI: 10.1158/1541-7786.MCR-20-0867
Abstrakt: Activating protein 2 alpha (AP-2α; encoded by TFAP2A ) functions as a tumor suppressor and influences response to therapy in several cancer types. We aimed to characterize regulation of the transcriptome by AP-2α in colon cancer. CRISPR-Cas9 and short hairpin RNA were used to eliminate TFAP2A expression in HCT116 and a panel of colon cancer cell lines. AP-2α target genes were identified with RNA sequencing and chromatin immunoprecipitation sequencing. Effects on cell cycle were characterized in cells synchronized with aphidicolin and analyzed by FACS and Premo FUCCI. Effects on invasion and tumorigenesis were determined by invasion assay, growth of xenografts, and phosphorylated histone H3 (PHH3). Knockout of TFAP2A induced significant alterations in the transcriptome including repression of TGM2 , identified as a primary gene target of AP-2α. Loss of AP-2α delayed progression through S-phase into G 2 -M and decreased phosphorylation of AKT, effects that were mediated through regulation of TGM2 . Buparlisib (BKM120) repressed in vitro invasiveness of HCT116 and a panel of colon cancer cell lines; however, loss of AP-2α induced resistance to buparlisib. Similarly, buparlisib repressed PHH3 and growth of tumor xenografts and increased overall survival of tumor-bearing mice, whereas, loss of AP-2α induced resistance to the effect of PI3K inhibition. Loss of AP-2α in colon cancer leads to prolonged S-phase through altered activation of AKT leading to resistance to the PI3K inhibitor, Buparlisib. The findings demonstrate an important role for AP-2α in regulating progression through the cell cycle and indicates that AP-2α is a marker for response to PI3K inhibitors. IMPLICATIONS: AP-2α regulated cell cycle through the PI3K cascade and activation of AKT mediated through TGM2. AP-2α induced sensitivity to Buparlisib/BKM120, indicating that AP-2α is a biomarker predictive of response to PI3K inhibitors.
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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