ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97

Pozner, A.; Verma, S. P.; Li, L.; Wang, S.; Barrott, J. J.; Nelson, M. L.; Yu, J. S. E.; Negri, G. L.; Colborne, S.; Hughes, C. S.; Zhu, J.-F.; Lambert, S. L.; Carroll, L. S.; Smith-Fry, K.; Stewart, M. G.; Kannan, S.; Jensen, B.; Mortenson, K. L.; John, C.; Sikdar, S.; Liu, H.; Dang, N. H.; Bourdage, J.; Li, J.; Vahrenkamp, J. M.; Groundland, J. S.; Wustrack, R.; Senger, D. L.; Zemp, F. J.; Mahoney, D. J.; Gertz, J.; Zhang, X.; Lazar, A. J.; Hirst, M.; Morin, G. B.; Nielsen, T. O.; Shen, P. S.; Jones, K. B.

doi:10.1101/2023.09.29.560242

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bioRxiv · 10.1101/2023.09.29.560242

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97

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Abstract

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCPs potential as a novel therapeutic target.

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Pozner, A., Verma, S. P., Li, L., Wang, S., Barrott, J. J., Nelson, M. L., Yu, J. S. E., Negri, G. L., Colborne, S., Hughes, C. S., Zhu, J.-F., Lambert, S. L., Carroll, L. S., Smith-Fry, K., Stewart, M. G., Kannan, S., Jensen, B., Mortenson, K. L., John, C., Sikdar, S., Liu, H., Dang, N. H., Bourdage, J., Li, J., Vahrenkamp, J. M., Groundland, J. S., Wustrack, R., Senger, D. L., Zemp, F. J., Mahoney, D. J., Gertz, J., Zhang, X., Lazar, A. J., Hirst, M., Morin, G. B., Nielsen, T. O., Shen, P. S., Jones, K. B.. 2023-10-02. ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97. https://doi.org/10.1101/2023.09.29.560242

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