TY - JOUR
T1 - DAXX drives de novo lipogenesis and contributes to tumorigenesis
AU - Mahmud, Iqbal
AU - Tian, Guimei
AU - Wang, Jia
AU - Hutchinson, Tarun E.
AU - Kim, Brandon J.
AU - Awasthee, Nikee
AU - Hale, Seth
AU - Meng, Chengcheng
AU - Moore, Allison
AU - Zhao, Liming
AU - Lewis, Jessica E.
AU - Waddell, Aaron
AU - Wu, Shangtao
AU - Steger, Julia M.
AU - Lydon, McKenzie K.L.
AU - Chait, Aaron
AU - Zhao, Lisa Y.
AU - Ding, Haocheng
AU - Li, Jian Liang
AU - Purayil, Hamsa Thayele
AU - Huo, Zhiguang
AU - Daaka, Yehia
AU - Garrett, Timothy J.
AU - Liao, Daiqing
N1 - Funding Information:
We thank Shuang Huang and Maria Zajac-Kaye for providing reagents, Subramaniam Shyamalagovindarajan and Ranjan Perera for high throughput sequencing for the ChIP-seq experiments (supported the grant 5BC08 from Bankhead-Coley Cancer Research Program, Florida Department of Health to Perara). This work was supported by grants from Bankhead-Coley Cancer Research Program (4BF02 and 6BC03), and James and Esther King Biomedical Research Program (6JK03, 20K07, 21K03, and 22K05), Florida Department of Health, Florida Breast Cancer Foundation, and UF Health Cancer Center (to D. Liao). Mass spectrometry-based global lipidomics work was supported by grant from National Institutes of Health (U24DK097209 to T.G.). J. Li was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-37501-0
DO - 10.1038/s41467-023-37501-0
M3 - Article
C2 - 37045819
AN - SCOPUS:85152335764
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1927
ER -