UBR5's mechanisms of action in tumorigenesis and immunoregulation

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Clinical analyses show that UBR5 gene amplifications and overexpression occur in 10-40% cases of many major types of aggressive human cancers. Furthermore, breast, ovarian and prostate cancer patients carrying genetic alterations in UBR5 have significantly reduced survivals compared to those without the lesions. Our experimental work in vitro and in vivo has first demonstrated that UBR5, functioning like an “oncogene”, plays a profound role in promoting breast and ovarian cancer growth and metastasis. We have also shown that tumor-derived UBR5 drives malignant triple negative mammary tumor growth through both cell-intrinsic and extrinsic mechanisms, whereas it facilitates metastasis primarily in a tumor cell-autonomous manner. Thus, further elucidating UBR5’s fundamental biology and identifying critical signaling nodules controlled by UBR5 in its potent tumorigenic and immunoregulatory activities will not only advance the science but also help the development of novel therapies for highly malignant breast cancer that evades the endogenous cellular control mechanisms and resist current interventional strategies. We hypothesize that UBR5 promotes aggressive BC/TNBC via distinct mechanisms that include controlling the CDC73 protein turnover in an E3 ubiquitin ligase-dependent manner and enhancing Interferon-g-induced transcription of the PDL1 gene and others in an E3 ligase- independent manner. We propose to broaden and expand the exploration of the cellular and molecular mechanisms of these modulations in two major specific aims. (1) To characterize the biochemical basis of CDC73 protein regulation by UBR5 acting as an E3 ubiquitin ligase; and investigate the role of the chemokine CXCL16 in mediating CDC73’s immunostimulatory activities via recruitment of cytotoxic T lymphocytes to the tumor site. (2) To investigate the cellular and molecular mechanism whereby UBR5 broadly enhances the IFN--activated signaling pathway independently of the E3 ligase activity and explore the therapeutic potential of pharmacological UBR5 inhibition. The outcome of these studies will pave the way for developing innovative therapeutic strategies for highly aggressive and therapy-resistant breast cancer by targeting UBR5 and/or its crucial signaling pathways.