Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma. (20th September 2018)

• Record Type: Journal Article
• Authors: Hartleben, Götz; Müller, Christine; Krämer, Andreas; Schimmel, Heiko; Zidek, Laura M; Dornblut, Carsten; Winkler, René; Eichwald, Sabrina; Kortman, Gertrud; Kosan, Christian; Kluiver, Joost; Petersen, Iver; van den Berg, Anke; Wang, Zhao‐Qi; Calkhoven, Cornelis F
• Is Part Of: EMBO journal. Volume 37:Number 21(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-09-20
• Subjects: Burkitt's lymphoma -- cancer -- mTORC1 -- MYC -- TSC1/2; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798589
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Although generally associated with tumor suppression, the negative mTOR regulators TSC1/2 are appropriated by the MYC oncogene to prevent mTORC1 hyperactivation that may otherwise jeopardize survival of MYC‐driven cancers. The Tuberous sclerosis complex (TSC) is highly expressed in MYC‐driven Burkitt′s Lymphoma (BL) and is required for BL cell survival. MYC maintains high TSC1/2 expression in BL cells through transcriptional and post‐transcriptional upregulation of TSC1. In combination with high MYC expression in BL, mTORC1 hyperactivation upon TSC loss‐of‐function leads to elevated mitochondrial respiration, toxic ROS production, and apoptosis. The tumor maintenance function of TSC in BL questions a general role of the TSC as a tumor suppressor. Abstract : Although generally associated with tumor suppression, the mTOR regulators TSC1/2 are appropriated by the MYC oncogene to prevent mTORC1 hyperactivation that may otherwise jeopardize survival of MYC‐driven cancers.