KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition
| Autor: | Robert E. Lewis, Robert A. Svoboda, Kurt W. Fisher, Chaitra Rao, Hans Clevers, Chittibabu Guda, Adrian R. Black, Siddesh Southekal, Tomohiro Mizutani, Danielle E. Frodyma, Keith R. Johnson |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Colorectal cancer human organoids Protein Kinases/genetics Metastasis 0302 clinical medicine Neoplasm Proteins/genetics Cell Movement Translational regulation Biology (General) Cancer Biology Tumor biology Chemistry General Neuroscience Cell migration Translation (biology) General Medicine Cadherins Phenotype Neoplasm Proteins Cell biology Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Medicine colon cancer cells Signal transduction Colorectal Neoplasms Research Article Human Epithelial-Mesenchymal Transition Slug QH301-705.5 MAP Kinase Signaling System Science Repressor General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Cell Line Tumor medicine Humans Neoplasm Invasiveness Epithelial–mesenchymal transition Neoplastic General Immunology and Microbiology Cadherins/genetics Cancer Cell Biology medicine.disease biology.organism_classification 030104 developmental biology Gene Expression Regulation Cancer cell Protein Kinases Transcription Factors |
| Zdroj: | eLife, 10. eLife Sciences Publications eLife, Vol 10 (2021) eLife |
| ISSN: | 2050-084X |
| Popis: | The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior. eLife digest The majority of cancer deaths result from tumor cells spreading to other parts of the body via a process known as metastasis. 90% of all cancers originate in epithelial cells that line the inner and outer surface of organs in our bodies. Epithelial cells, however, are typically stationary and must undergo various chemical and physical changes to transform in to migratory cells that can invade other tissues. This transformation process alters the amount of protein cells use to interact with one another. For example, epithelial cells from the colon produce less of a protein called E-cadherin as they transition into migrating cancer cells and make another protein called N-cadherin instead. A protein called KSR1 is a key component of a signaling pathway that is responsible for generating the proteins colon cancer cells need to survive. But it is unknown which proteins KSR1 helps synthesize and whether it plays a role in the metastasis of colon cancer cells. To investigate this, Rao et al. studied the proteins generated by cancerous colon cells cultured in the laboratory, in the presence and absence of KSR1. The experiment showed that KSR1 increases the levels of a protein called EPSTI1, which colon cancer cells need to transform into migratory cells. Depleting KSR1 caused cancer cells to generate less EPSTI1 and to share more features with healthy cells, such as higher levels of E-cadherin on their surface and reduced mobility. Adding EPSTI1 to the cancer cells that lacked KSR1 restored the traits associated with metastasis, such as high levels of N-cadherin, and allowed the cells to move more easily. These findings suggest that KSR1 and EPSTI1 could be new drug targets for reducing, or potentially reversing, the invasive behavior of colon cancer cells. However, further investigation is needed to reveal how EPSTI1 is generated and how this protein helps colon cancer cells move and invade other tissues. |
| Databáze: | OpenAIRE |
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