UC Davis

Nuclear receptor RAR-related orphan receptor gamma (RORγ) and its isoform RORγt are major transcriptional regulators in control of mammalian metabolism, circadian rhythm, and immune responses. Recent studies have highlighted their significant roles in tumor development and progression in different cancer types, including cancers of prostate, breast, pancrease and lung. Despite being initially recognized as an orphan receptor, recent studies have unveiled many small-molecule modulators targeting RORγ/RORγt. In my dissertation studies, I investigated the cell growth-inhibitory effects of several synthetic compounds, including VTP-23, TAK828F, XY018, and GSK805 and found that they display distinct and sometimes contrasting activities in a tissue or cell-specific manner. Specifically, VTP-23 and TAK828F effectively inhibit the inflammatory gene program in Th17 cells but exhibit limited potency in inhibiting triple-negative breast cancer (TNBC) tumor cell growth. Conversely, antagonists such as XY018 and GSK805 effectively suppress tumor cell growth but modestly affect the cytokine expression in Th17 cells. My further investigations uncovered distinct chromatin accessibility alteration elicited by the RORγ modulators as a key determinant in their tissue selectivity. Similar tissue-specific activities were also observed in natural compounds targeting RORγ, such as ursolic acid (UA) and digoxin. I found that UA inhibits RORγ-dependent transactivation function, leading to the down-regulation of AR signaling in prostate cancer cells and cholesterol biosynthesis gene programs in TNBC cells. In contrast, digoxin does not affect RORγ-controlled gene programs in TNBC cells and instead up-regulates AR signaling in prostate cancer cells. These novel findings not only illustrate, for the first time, the tissue-dependent, context-specific activities of the RORγ-targeting compounds but also suggest that the mechanisms of RORγ-function in regulation of specific gene programs are tissue/cell-context dependent. Also, they will likely be valuable information for future development of RORγ-targeting compounds with context-specific activities that are tailored to the disease treatment, including unique compounds that act as agonists in certain tissue or cells (e.g. some immune cells) and at the same time as potent antagonists in other tissue or cells (e.g. cancer cells). Such dual strategy may hold great promise for effectively treatment of different cancer types where RORγ plays a crucial role in the disease progression.