Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors
Dimitris Karagiannis,
Warren Wu,
Albert Li,
Makiko Hayashi,
Xiao Chen,
Michaela Yip,
Vaibhav Mangipudy,
Xinjing Xu,
Francisco J. Sánchez-Rivera,
Yadira M. Soto-Feliciano,
Jiangbin Ye,
Thales Papagiannakopoulos,
Chao Lu
Affiliations
Dimitris Karagiannis
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Warren Wu
Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
Albert Li
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
Makiko Hayashi
Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
Xiao Chen
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Michaela Yip
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Vaibhav Mangipudy
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Xinjing Xu
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Francisco J. Sánchez-Rivera
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Yadira M. Soto-Feliciano
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Jiangbin Ye
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
Thales Papagiannakopoulos
Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
Chao Lu
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Corresponding author
Summary: The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.
