The hidden switches underlying 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 tumor-suppressive) roles depending on experimental conditions. To elucidate the mechanisms underlying such contrasting roles of PGE2 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 cells. 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 cell proliferation and thereby being a promising anti-cancer therapeutic target.
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Dongkwan
D
Shin
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, Republic of Korea.
Ik Soo
IS
Kim
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, Republic of Korea.
Ji Min
JM
Lee
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Sung-Young
SY
Shin
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Jong-Hoon
JH
Lee
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, Republic of Korea ckh@kaist.ac.kr sbaek@snu.ac.kr.
Sung Hee
SH
Baek
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea ckh@kaist.ac.kr sbaek@snu.ac.kr.
Kwang-Hyun
KH
Cho
D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008962:Models, Theoretical; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C539738:RORA protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D051571:Protein Kinase C-alpha; D015232:Dinoprostone
RORα, mathematical modeling; Wnt signaling; biphasic response; colorectal cancer; hysteresis; systems biology