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Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma
Götz Hartleben1,2, Christine Müller1,2, Andreas Krämer2
1European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
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.
Insights
Tuberous sclerosis complex (TSC) 1/2, usually a tumor suppressor, is highly expressed in Burkitt
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tuberous sclerosis complex (TSC) 1/2 typically suppresses tumors by inhibiting mTORC1.
- Loss of TSC1 or TSC2 function is uncommon in malignant tumors, despite their tumor-suppressive roles.
Purpose of the Study:
- To investigate the role of TSC1/2 in Burkitt's lymphoma, a MYC-driven cancer.
- To elucidate the mechanism by which MYC influences TSC1 expression and its downstream effects.
- To explore potential therapeutic strategies targeting TSC1/2 or mTORC1 in Burkitt's lymphoma.
Main Methods:
- Analysis of TSC1/2 expression in Burkitt's lymphoma cell lines and patient samples.
- Investigating MYC's transcriptional regulation of TSC1 and miR-15a.
- Assessing the impact of TSC1 knockdown on mTORC1 activity, ROS production, and apoptosis.
- Evaluating tumor growth in a xenograft mouse model following TSC1 deficiency.
Main Results:
- TSC1/2 is highly expressed in Burkitt's lymphoma.
- MYC induces TSC1 expression transcriptionally and represses miR-15a.
- TSC1 knockdown increases mTORC1 activity, ROS production, and apoptosis, while reducing tumor growth.
- TSC1 deficiency attenuates tumor growth in vivo.
Conclusions:
- TSC1 plays a critical role in maintaining MYC/mTORC1 homeostasis for Burkitt's lymphoma cell survival.
- TSC1/2 inhibition or mTORC1 hyperactivation presents a novel therapeutic avenue for MYC-driven cancers.