Gucciardo, E. | bioRxiv Science

bioRxiv2020

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer in need for novel therapies. Here we show that the PROX1 transcription factor, which is essential for normal myoblast differentiation, is highly expressed in RMS tumors. We demonstrate that PROX1 is needed for RMS cell stemness and growth in vitro, and for RMS tumor formation in mouse xenograft models. In addition, we unveil that PROX1 is an essential for myogenic properties in RMS. PROX1 depletion reprogrammed the RMS transcriptome to resemble benign mesenchymal stem cells and repressed many of the previously identified RMS effector transcripts and myogenic genes. By using proximity labeling and mass spectrometry, we found that PROX1 interacts with the NuRD and CoREST complexes containing class I HDACs. Our studies reveal a major role of PROX1-HDAC interaction in RMS and give insights that inhibiting this interaction could be a promising therapeutic approach.

cancer biology↗

bioRxiv2018

FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases MST1/2 has been linked to apoptosis and tumor suppression via YAP/Hippo pathway dependent and independent mechanisms. With a kinase substrate screen we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as reflected by increased autophosphorylation at T183 in FGFR4 overexpressing MDA-MB-231 cells. Importantly, the specific short-term inhibition or knockdown of FGFR4 also led to MST1/2 activation in conjunction with induction of MST1/2-dependent apoptosis in an endogenous model of HER2+ breast cancer cells. Moreover, FGFR4 knockdown increased the level of active nuclear MST1 coincidentally with cell polarization and membrane-association of YAP in three-dimensional breast cancer cell spheres. Consistently, FGFR4 overexpression correlated with reduced Hippo pathway-mediated, nuclear translocation-inhibiting YAP phosphorylation, and abysmal HER2+ breast carcinoma patient outcome in TCGA cohort. Our results reveal a novel mechanism for FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-dependent apoptosis machinery in the tumor cells with prominent HER/ERBB signaling driven proliferation.

cancer biology↗