Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells
Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells
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DOI：
10.1128/mcb.00012-17
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发表时间：
2017-08-01
影响因子：
5.3
通讯作者：
Nishida, Eisuke
中科院分区：
文献类型：
--
作者：
Imajo, Masamichi;Kondoh, Kunio;Nishida, Eisuke
RAS/细胞外信号调节激酶（ERK）信号传导的失调激活和视黄酸受体（RAR）信号传导的缺陷都涉及许多类型的癌症。然而，这些改变在调节癌细胞命运中的相互关系尚未完全阐明。在这里，我们表明RAS/ERK和RAR信号通路相互拮抗，以调节结直肠癌（CRC）细胞的命运。我们发现RAR信号的激活促进CRC细胞的自发分化，而ERK的激活抑制它。我们的微阵列分析确定其表达水平上调RAR信号的基因。值得注意的是，这些基因之一，MKP 4，编码促分裂原活化蛋白（MAP）激酶的双特异性磷酸酶的成员，介导RAR激活后ERK失活，从而促进CRC细胞的分化。此外，我们的研究结果还表明，RA诱导RAR靶基因被ERK通路激活抑制。这种抑制来自RAR转录活性的抑制，其显示通过RIP 140/组蛋白脱乙酰酶（HDAC）介导的机制介导。这些结果确定了RAS/ERK和RAR信号在CRC细胞的细胞命运决定中的拮抗相互作用，并定义了其潜在的分子机制。
Deregulated activation of RAS/extracellular signal-regulated kinase (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, encoding a member of dual-specificity phosphatases for mitogen-activated protein (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 an RIP140/histone deacetylase (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.