Regulation of differentiation and invasion in RMS by ASAP1

Division Of Basic Sciences - Nci

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Abstract

In this project, we identified a role in FN-RMS differentiation for ASAP1, an ARF GTPase-activating protein (ARF GAP) with pro-invasive and tumor suppressor functions. We found that knockdown of ASAP1 and its homologs, ASAP2 and ASAP3, inhibited differentiation in myoblasts and FN-RMS cells. Interestingly, knockdown of ARF1 or ARF5 also blocked differentiation of FN-RMS, further validating the role of the ARF pathway in FN-RMS differentiation. We discovered that ASAP1 loss blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation, nuclear exclusion, and inactivation of WWTR1 (TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1 that is regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation and restored nuclear localization, which inhibited MEKi-induced differentiation. This project showed that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. In addition, this project supports YAP1/TAZ inhibition as a strategy for FN-RMS differentiation therapy. This project was published in Molecular Cancer Research.