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

Gizaw, N. Y.; Kallio, P.; Punger, T.; Kinnunen, M.; Gucciardo, E.; Lehti, K.; Haglund, C.; Bohling, T.; Varjosalo, M.; Sampo, M.; Alitalo, K.; Kivela, R.

2020-04-20 cancer biology
10.1101/2020.04.19.045989 bioRxiv
Show abstract

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.

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