shRNA drop-out screen identifies BRD4 targeting transcription from RNA polymerase II system to activate β-catenin to promote soft-tissue tumor proliferations

Abstract

BRD4 (Bromodomain containing protein 4) is a chromatin reader binds to acetylated lysine residues on histones interacting with RNA Pol II, p-TFeb. PDGF-BB was presented here, in soft-tissue tumor, as an oncogenic factor driving cell proliferation, and aberrant BRD4 knockdown significantly reduced tumor aggressiveness and unfavorable prognosis in soft-tissue tumors. To identify suppressive key drivers impeding demoid tumor growth, shRNA drop-out screen analysis identified signature of “transcription from RNA polymerase II promoter” including DDX, Stat3, SMARCA, ATM, SIRT1, cMyc that were recruited with BRD4 interation in activating β-catenin, which is a major key driver mutated in soft-tissue tumor, and its depletion ceased soft-tissue tumor cell growth. Sepcifically, BRD4 mediated PDGF-BB signaling in GSK stimulation through transcriptional regulation from RNA polymerase II activity with PI3K as target, and thus not only canonical β -catenin/TCF4 signaling, but also non-canonical β -catenin conjunction complex response was activated by BRD4 in nucleus involved in promoting cell proliferation. Our study delineated a signaling axis that may allow soft-tissue tumor cells to escape apoptosis during colonization by activating PDGFBB-BRD4-GSK-β -catenin and non-canonical-β-catenin pathway through BRD4 in cancer cells. An efficient treatment for soft-tissue tumors could be accomplished by targeting PDGF and BRD4 survival pathways on soft-tissue tumor cells.