PD37-01 LOSS OF FOXA1 RESULTS IN GENOME-WIDE EPIGENETIC REPROGRAMMING AND ACTIVATION OF INTERFERON-RESPONSE GENES INCLUDING <i>CD274</i> /PD-L1

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-01 LOSS OF FOXA1 RESULTS IN GENOME-WIDE EPIGENETIC REPROGRAMMING AND ACTIVATION INTERFERON-RESPONSE GENES INCLUDING CD274/PD-L1 Hironobu Yamashita, Wenhuo Hu, Joshua Warrick, Vonn Walter, Jenna Craig, Hikmat Al-Ahmadie, and David Degraff YamashitaHironobu Yamashita More articles by this author , HuWenhuo Hu WarrickJoshua Warrick WalterVonn Walter CraigJenna Craig Al-AhmadieHikmat Al-Ahmadie DegraffDavid View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION OBJECTIVE: Forkhead Box A1 (FOXA1) is a pioneer transcription factor (TF) critical in epigenetic regulation chromatin state cell fate determination. Reduced an independent predictor poor overall survival bladder cancer (BC) patients. However, the impact loss on epigenetics BC unknown. Therefore, we determined KO modification associated gene expression. Our integrated analysis identifies as important regulator expression immune checkpoint (IC) targets BC. METHODS: We used CRISPR/Cas9 delete human luminal cells. performed RNA-seq Chip-seq for H3K27ac, mark active enhancers/promoters. Motif GSEA RNA/Chip-seq were identify KO-induced differences influencing Western blotting (WB)/qPCR confirmed FOXA1-mediated In silico TCGA data also relevance disease. RESULTS: identified 8,230 differentially expressed genes KO. Notably, IFNɑ/ɣ signatures enriched As expected, majority H3K27ac across genomic areas mapped intergenic (n=6,250 peaks; 42% total peaks) intronic (n=6,490; 43%) regions. addition, differential levels proximal promoters (n=1,306; 9%) well within bodies (n=931; 6%). Integrated RNA/ChIP-seq shows changes are mirrored H3K27ac. DNA sequence significant increases TF binding motifs including interferon (IFN) sensitive response element (ISRE) IFN factors such IRF1. Moreover, increased regulatory elements being with several upregulated ISGs These include ISG15, IFIT2/3, IFI44L CD274/PD-L1. WB/qPCR upregulation ISGs, following Analysis inverse relationship between CD274 other cancers. CONCLUSIONS: summary, provide evidence widespread reprogramming after Additionally, that contribute activation global IFN-dominant signature, cell-intrinsic manner Source Funding: Supported part RSG 17-233–01-TBE from American Cancer Society (D.J.D.), The W.W. Smith Charitable Trust Ruth Heisey Cagnoli Endowment Urology at Penn State College Medicine Bladder Support Group Health © 2021 Urological Association Education Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e655-e655 Advertisement Copyright Permissions© Inc.MetricsAuthor Information Expand Loading ...