LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis.
Bottom Line: The positive transcription elongation factor b (P-TEFb) stimulates transcriptional elongation by phosphorylating Pol II and antagonizing negative elongation factors.A reservoir of P-TEFb is sequestered in the inactive 7SK snRNP where 7SK snRNA and the La-related protein LARP7 are required for the integrity of this complex.Decreased levels of LARP7 and 7SK snRNA redistribute P-TEFb to the transcriptionally active super elongation complex, resulting in P-TEFb activation and increased transcription of EMT transcription factors, including Slug, FOXC2, ZEB2, and Twist1, to promote breast cancer EMT, invasion, and metastasis.
Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.Show MeSH
Related in: MedlinePlus
Mentions: If LARP7 downregulation accelerates malignant progression by increasing expression of EMT genes through elevated P-TEFb activity, we should expect P-TEFb inhibition or re-introduction of LARP7 protein to block EMT and transformation. To test this hypothesis, we first treated the highly invasive and metastatic MDA-MB-231 breast cancer cells with flavopiridol and noted that the treatment significantly inhibited cell migration (Figure 7A). Furthermore, mRNA levels of Slug, a major EMT regulator, were repressed in a dose-dependent manner upon P-TEFb inhibition (Figure 7B). These data suggest that inhibition of P-TEFb can effectively block cell migration in metastatic breast cancer cells.10.7554/eLife.02907.012Figure 7.Inhibition of P-TEFb impairs EMT and survival of metastatic MDA-MB-231 cells.
Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.