The hidden switches undertying RORα-mediated circuits that critically regulate uncontrolled cell proliferation

Prostaglandin E2 （PGE2） is known to have a key role in the development of colorectal cancer, but previous experiments showed its contrasting （i.e. tumor-promoting or tu mor-suppressive） roles depending on experimental conditions. To elucidate the mechanisms underlying such contrasting roles of PG E2 in tumorigenesis, we investigated all the previous experiments and found a new signal transduction pathway mediated by retinoic acid receptor-related orphan receptor （ROR）α, in which PGE2/PKCα-dependent phosphorylation of RORα attenuates Wnt target gene expression in colon cancer ceils. From mathematical simulations combined with biochemical experimentation, we revealed that RORα induces a biphasic response of Wnt target genes to PGE2 stimulation through a regulatory switch formed by an incoherent feedforward loop, which provides a mechanistic explanation on the contrasting roles of PGE2 observed in previous experiments. More interestingly, we found that RORα constitutes another regulatory switch formed by coupled positive and negative feedback loops, which regulates the hysteretic response of Wnt signaling and eventually converts a proliferative cellular state into an anti-proliferative state in a very delicate way. Our results indicate that RORα is the key regulator at the center of these hidden switches that critically regulate cancer celt proliferation and thereby being a promising anti-cancer therapeutic target.