Antagonism between retinoic acid and ERK MAPK signaling

What is it about?

Deregulated activation of RAS/ERK signaling and defects in retinoic acid receptor (RAR) signaling are both implicated in many types of cancers. However, interrelationships between these alterations in regulating cancer cell fates have not been fully elucidated. Here, we show that RAS/ERK and RAR signaling pathways antagonistically interact with each other to regulate colorectal cancer (CRC) cell fates. We show that RAR signaling activation promotes spontaneous differentiation of CRC cells, while ERK activation suppresses it. Our microarray analyses identify genes whose expression levels are upregulated by RAR signaling. Notably, one of these genes, MKP4, a member of dual-specificity phosphatases for MAP kinases, mediates ERK inactivation upon RAR activation, thereby promoting the differentiation of CRC cells. Moreover, our results also show that RA-induction of RAR-target genes is suppressed by the ERK pathway activation. This suppression results from the inhibition of RAR transcriptional activity, which is shown to be mediated through a RIP140/HDAC-mediated mechanism. These results identify antagonistic interactions between RAS/ERK and RAR signaling in the cell fate decision of CRC cells, and define their underlying molecular mechanisms.

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Why is it important?

Retinoic acid (RA), an active derivative of vitamin A, plays an important role in the development and homeostasis of many vertebrate tissues through its regulatory effects on cell proliferation, differentiation and apoptosis. Most of these effects are mediated by nuclear retinoid receptors, RA receptors (RARs) and retinoid X receptors (RXRs). As transcriptional activation of RAR often leads to inhibition of cell proliferation, loss of normal RAR function in the presence of physiological levels of RA is implicated in many types of cancers. Thus, treatment with pharmacological doses of retinoids, which results in the activation of RAR signaling, has been considered a promising strategy for cancer therapy and prevention. However, entire mechanisms by which RAR signaling exerts tumor-suppressive effects on many types of tumor have remained elusive. In addition, it has also remained unclear how normal RAR function is abolished during progression of these tumors. In this study, we showed that RAR signaling induces MKP4 expression to cause ERK inactivation in colorectal cancer cells. This finding might answer a long-standing question of how retinoids achieve tumor-suppressive effects, as the deregulated activation of ERK is among general mechanisms for cancer. Moreover, our results that ERK activation suppresses RAR transcriptional activity through a RIP140/HDAC-mediated mechanism could provide a clue to the elucidation of underlying mechanisms of the defects in RAR signaling in cancer cells. In addition, as the ERK and RAR signaling pathways are both involved in a wide variety of cellular functions, our findings concerning the interactions between the two signaling pathways should provide novel insights into molecular bases for many other physiological and pathological processes.