Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity
Eva Tsaousidou,
Jędrzej Chrzanowski,
Pascal Drané,
Grace Y. Lee,
Nadine Bahour,
Zeqiu Branden Wang,
Shijun Deng,
Zhe Cao,
Kaimeng Huang,
Yizhou He,
Mateusz Kaminski,
Dominika Michalek,
Ekin Güney,
Kalindi Parmar,
Wojciech Fendler,
Dipanjan Chowdhury,
Gökhan S. Hotamışlıgil
Affiliations
Eva Tsaousidou
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Jędrzej Chrzanowski
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
Pascal Drané
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Grace Y. Lee
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Nadine Bahour
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Zeqiu Branden Wang
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Shijun Deng
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Zhe Cao
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Kaimeng Huang
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Yizhou He
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Mateusz Kaminski
Department of General Surgery, Medical University of Lodz, 90-153 Lodz, Poland
Dominika Michalek
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
Ekin Güney
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Kalindi Parmar
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Wojciech Fendler
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
Dipanjan Chowdhury
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding author
Gökhan S. Hotamışlıgil
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding author
Summary: It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
