RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity

• Published in: International journal of molecular sciences 2019-04, Vol.20 (8), p.1994
• Main Authors: Yoo, Sun-Mi, Lee, Cheol-Jung, An, Hyun-Jung, Lee, Joo Young, Lee, Hye Suk, Kang, Han Chang, Cho, Sung-Jun, Kim, Seung-Min, Park, Juhee, Kim, Dae Joon, Cho, Yong-Yeon
• Format: Article
• Language: English
• Subjects: Adrenal glands; Amino acids; Angiogenesis; Apoptosis; Binding; Bone marrow; Breast cancer; c-Fos protein; Cancer; Cell activation; Cell adhesion & migration; Cell growth; Cell proliferation; cell signaling; cell transformation; Cytoplasm; ELK3; Esophagus; Extracellular signal-regulated kinase; Gene expression; Gene regulation; Glucose metabolism; Growth factors; Histone H3; Hypoxia; Kinases; Liver; Localization; Metastases; Metastasis; Muscles; Pharynx; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; protein–protein interaction; RSK2; Signal transduction; Skin; Trachea; Transcription factors; Transformations; Umbilical cord; Uterus; Vascular endothelial growth factor; Vascular tissue
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20081994

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.