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ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target.

ABSTRACT: ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered. Thus, in this review, we focus on summarizing the structural features and biological functions of ATAD2 from an epigenetic modulator to a cancer therapeutic target, and further discuss the existing small-molecule inhibitors targeting ATAD2 to improve potential cancer therapy. Together, these inspiring findings would shed new light on ATAD2 as a promising druggable target in cancer and provide a clue on the development of candidate anticancer drugs.

SUBMITTER: Fu J

PROVIDER: S-EPMC9830439 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target.

Fu Jiahui J Zhang Jin J Chen Xiya X Liu Zhiying Z Yang Xuetao X He Zhendan Z Hao Yue Y Liu Bo B Yao Dahong D

Theranostics 20230101 2

ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a pot ...[more]

PMID: 36632213

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Project description:The abundant homohexameric AAA + ATPase p97 (also known as valosin-containing protein, VCP) is highly conserved from Dictyostelium discoideum to human and a pivotal factor of cellular protein homeostasis as it catalyzes the unfolding of proteins. Owing to its fundamental function in protein quality control pathways, it is regulated by more than 30 cofactors, including the UBXD protein family, whose members all carry an Ubiquitin Regulatory X (UBX) domain that enables binding to p97. One member of this latter protein family is the largely uncharacterized UBX domain containing protein 9 (UBXD9). Here, we analyzed protein-protein interactions of D. discoideum UBXD9 with p97 using a series of N- and C-terminal truncation constructs and probed the UBXD9 interactome in D. discoideum. Pull-down assays revealed that the UBX domain (amino acids 384-466) is necessary and sufficient for p97 interactions and that the N-terminal extension of the UBX domain, which folds into a β0-α- 1-α0 lariat structure, is required for the dissociation of p97 hexamers. Functionally, this finding is reflected by strongly reduced ATPase activity of p97 upon addition of full length UBXD9 or UBXD9261-573. Results from Blue Native PAGE as well as structural model prediction suggest that hexamers of UBXD9 or UBXD9261-573 interact with p97 hexamers and disrupt the p97 subunit interactions via insertion of a helical lariat structure, presumably by destabilizing the p97 D1:D1' intermolecular interface. We thus propose that UBXD9 regulates p97 activity in vivo by shifting the quaternary structure equilibrium from hexamers to monomers. Using three independent approaches, we further identified novel interaction partners of UBXD9, including glutamine synthetase type III as well as several actin-binding proteins. These findings suggest a role of UBXD9 in the organization of the actin cytoskeleton, and are in line with the hypothesized oligomerization-dependent mechanism of p97 regulation.

Dataset Information

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target.

Publications

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target.

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