Abstract
Raf kinase inhibitory protein (RKIP), also known as a phosphatidylethanolamine-binding protein 1 (PEBP1), functions as a tumor suppressor and regulates several signaling pathways, including ERK and NF-B. RKIP is severely downregulated in human malignant cancers, indicating a functional association with cancer metastasis and poor prognosis. The transcription regulation of RKIP gene in human cancers is not well understood. In this study, we suggested a possible transcription mechanism for the regulation of RKIP in human cancer cells. We found that Metadherin (MTDH) significantly repressed the transcriptional activity of RKIP gene. An analysis of publicly available datasets showed that the knockdown of MTDH in breast and endometrial cancer cell lines induced the expression RKIP. In addition, the results obtained from qRT-PCR and ChIP analyses showed that MTDH considerably inhibited RKIP expression. In addition, the RKIP transcript levels in MTDH-knockdown or MTDH-overexpressing MCF-7 cells were likely correlated to the protein levels, suggesting that MTDH regulates RKIP expression. In conclusion, we suggest that MTDH is a novel factor that controls the RKIP transcription, which is essential for cancer progression.
Highlights
Raf Kinase Inhibitory Protein (RKIP; called phosphatidylethanolamine-binding protein 1 (PEBP1)) was first elucidated as a binding protein of Raf1, a key regulator in mitogen-activated protein kinase (MAPK)pathways
We found that the expression of MTDH was significantly higher in tumor tissues compared to control tissues (Figure 1A)
Several previous studies suggest that MTDH could contribute to cancer progression, and it is considered a hallmark protein of metastatic cancers
Summary
Raf Kinase Inhibitory Protein (RKIP; called PEBP1) was first elucidated as a binding protein of Raf, a key regulator in mitogen-activated protein kinase (MAPK)pathways. Low expression of RKIP protein has been reported in many human cancers, including metastatic prostate, breast, and colon cancers, hepatocellular carcinoma, melanomas, and insulinomas [2]. Lack of RKIP protein activates the MEK/ERK pathway, promoting cell proliferation, survival, differentiation, and migration during cancer progression [3,4,5]. The mechanism responsible for the low expression of RKIP in human cancers is not well understood. One possible mechanism for the low intracellular level of RKIP in human diseases could involve reducing the RKIP gene transcription. To test this possibility, we investigated transcription factors and co-factors that directly or indirectly regulate the expression of the RKIP gene
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