DAXX drives de novo lipogenesis and contributes to tumorigenesis

Iqbal Mahmud, Guimei Tian, Jia Wang, Tarun E. Hutchinson, Brandon J. Kim, Nikee Awasthee, Seth Hale, Chengcheng Meng, Allison Moore, Liming Zhao, Jessica E. Lewis, Aaron Waddell, Shangtao Wu, Julia M. Steger, McKenzie L. Lydon, Aaron Chait, Lisa Y. Zhao, Haocheng Ding, Jian-Liang Li, Hamsa Thayele Purayil, Zhiguang Huo, Yehia Daaka, Timothy J. Garrett and Daiqing Liao ()
Additional contact information
Iqbal Mahmud: University of Florida College of Medicine
Guimei Tian: University of Florida College of Medicine
Jia Wang: University of Florida College of Medicine
Tarun E. Hutchinson: University of Florida College of Medicine
Brandon J. Kim: University of Florida College of Medicine
Nikee Awasthee: University of Florida College of Medicine
Seth Hale: University of Florida College of Medicine
Chengcheng Meng: University of Florida College of Medicine
Allison Moore: University of Florida College of Medicine
Liming Zhao: University of Florida College of Medicine
Jessica E. Lewis: University of Florida College of Medicine
Aaron Waddell: University of Florida College of Medicine
Shangtao Wu: University of Florida College of Medicine
Julia M. Steger: University of Florida College of Medicine
McKenzie L. Lydon: University of Florida College of Medicine
Aaron Chait: University of Florida College of Medicine
Lisa Y. Zhao: University of Florida College of Medicine
Haocheng Ding: University of Florida
Jian-Liang Li: National Institute of Environmental Health Sciences
Hamsa Thayele Purayil: University of Florida College of Medicine
Zhiguang Huo: University of Florida
Yehia Daaka: University of Florida College of Medicine
Timothy J. Garrett: University of Florida
Daiqing Liao: University of Florida College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that control their expression remain poorly understood. Using integrated transcriptomic, lipidomic, and molecular studies, here we report that DAXX is a regulator of oncogenic lipogenesis. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipogenesis, and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and DAXX mutants unable to bind SREBP1/2 have weakened activity in promoting lipogenesis and tumor growth. Remarkably, a DAXX mutant deficient of SUMO-binding fails to activate SREBP1/2 and lipogenesis due to impaired SREBP binding and chromatin recruitment and is defective of stimulating tumorigenesis. Hence, DAXX’s SUMO-binding activity is critical to oncogenic lipogenesis. Notably, a peptide corresponding to DAXX’s C-terminal SUMO-interacting motif (SIM2) is cell-membrane permeable, disrupts the DAXX-SREBP1/2 interactions, and inhibits lipogenesis and tumor growth. These results establish DAXX as a regulator of lipogenesis and a potential therapeutic target for cancer therapy.

Date: 2023
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DOI: 10.1038/s41467-023-37501-0

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