Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma

Götz Hartleben, Christine Müller, Andreas Krämer, Heiko Schimmel, Laura M Zidek, Carsten Dornblut, René Winkler, Sabrina Eichwald, Gertrud Kortman, Christian Kosan, Joost Kluiver, Iver Petersen, Anke van den Berg, Zhao-Qi Wang, Cornelis F Calkhoven

OnderzoeksoutputAcademicpeer review

8 Citaten (Scopus)
336 Downloads (Pure)

Samenvatting

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a. TSC1 knockdown results in elevated mTORC1-dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC-driven cancers.

Originele taal-2English
Artikelnummer98589
Aantal pagina's14
TijdschriftThe EMBO Journal
Volume37
Nummer van het tijdschrift21
Vroegere onlinedatum20-sep.-2018
DOI's
StatusPublished - 2-nov.-2018

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