DAXX drives de novo lipogenesis and contributes to tumorigenesis

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 tha...

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Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; p. 1927
Main Authors:	Mahmud, Iqbal, Tian, Guimei, Wang, Jia, Hutchinson, Tarun E., Kim, Brandon J., Awasthee, Nikee, Hale, Seth, Meng, Chengcheng, Moore, Allison, Zhao, Liming, Lewis, Jessica E., Waddell, Aaron, Wu, Shangtao, Steger, Julia M., Lydon, McKenzie L., Chait, Aaron, Zhao, Lisa Y., Ding, Haocheng, Li, Jian-Liang, Purayil, Hamsa Thayele, Huo, Zhiguang, Daaka, Yehia, Garrett, Timothy J., Liao, Daiqing
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 12-04-2023 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 13/109 13/44 13/89 14/19 14/63 38 38/15 38/39 49 49/90 49/91 631/67/1059/602 631/67/1347 631/80/304 64 64/60 82/29 82/80 Animals Binding Cancer Carcinogenesis - genetics Cell Transformation, Neoplastic Chromatin Co-Repressor Proteins - genetics Co-Repressor Proteins - metabolism Daxx protein Depletion Gene expression Humanities and Social Sciences Lipid metabolism Lipids Lipogenesis Lipogenesis - genetics Mice Molecular Chaperones - genetics Molecular Chaperones - metabolism multidisciplinary Mutants Neoplasms Science Science (multidisciplinary) Sterol Regulatory Element Binding Protein 1 - genetics Sterol Regulatory Element Binding Protein 1 - metabolism Sterol regulatory element-binding protein Therapeutic targets Transcriptomics Tumorigenesis Tumors
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Summary:	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. Cancer cells have altered lipid metabolism. Here the authors show that DAXX promotes lipogenesis and tumorigenesis through interaction with SREBP1/2.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-37501-0