Logo image
Back
AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer
Journal article   Open access   Peer reviewed

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

Anna C Beck, Edward Cho, Jeffrey R White, Lily Paemka, Tiandao Li, Vivian W Gu, Dakota T Thompson, Kelsey E Koch, Christopher Franke, Matthew Gosse, …
Molecular cancer research, Vol.19(7), pp.1156-1167
07/2021
DOI: 10.1158/1541-7786.MCR-20-0867
PMCID: PMC8254761
PMID: 33753551
url
https://doi.org/10.1158/1541-7786.MCR-20-0867View
Published (Version of record) Open Access

Abstract

Activating protein 2 alpha (AP-2α; encoded by ) 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 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 induced significant alterations in the transcriptome including repression of , identified as a primary gene target of AP-2α. Loss of AP-2α delayed progression through S-phase into G -M and decreased phosphorylation of AKT, effects that were mediated through regulation of . Buparlisib (BKM120) repressed 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.
 Aminopyridines - pharmacology Animals Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Line, Tumor Cell Survival - drug effects Cell Survival - genetics Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic - drug effects Gene Knockout Techniques HCT116 Cells Humans Mice Morpholines - pharmacology Phosphoinositide-3 Kinase Inhibitors - pharmacology RNA Interference RNA-Seq - methods S Phase - genetics Transcription Factor AP-2 - genetics Transcription Factor AP-2 - metabolism Xenograft Model Antitumor Assays - methods

Details

Metrics

18 Record Views
19 Times Cited - Web of Science
Logo image