Ovarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy.

01 Oct 2020·European review for medical and pharmacological sciences

MiR-200b-5p inhibits proliferation of ovarian cancer cells by targeting ATAD2 and regulating PI3K/AKT signaling pathway.

Article

Author: Xu, Y-H ; Dong, Y-Y ; Xie, P-M ; Lv, M ; Wang, A-Q

OBJECTIVEThe purpose of this study was to investigate the influences of micro ribonucleic acid (miR)-200b-5p on proliferation and apoptosis of ovarian cancer (OC) cells, and to explore its correlations with the target gene ATPase family, AAA domain containing 2 (ATAD2), and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.MATERIALS AND METHODSHuman ovarian fibroblasts (HOFs) or human OC cell lines (A2780) were cultured in vitro, and then, A2780 cells were separately transfected with miR-200b mimics or miR-NC or cultured with ATAD2-specific inhibitor BAY-850. Thereafter, the expression levels of miR-200b and ATAD2 messenger RNA (mRNA) were measured via qRT-PCR, and the proliferative capacity of cells was detected by CCK-8 assay. Next, the cell apoptosis was determined by means of flow cytometry and one-step TUNEL assay. Finally, the targeted regulatory relationship between miR-200b and ATAD2 was examined using a Luciferase reporter assay system, and the protein expressions were detected through Western blot (WB) assay.RESULTSIt was found that the expression level of miR-200b was remarkably lower (p<0.05), while the mRNA expression level of ATAD2 was notably higher (p<0.05) in A2780 cells than those in HOFs. The transfection with miR-200b mimics markedly reduced the mRNA expression level of ATAD2 (p<0.05) and the proliferative capacity (p<0.05) and increased the apoptosis rate (p<0.05) of A2780 cells. Besides, it was detected via the Luciferase reporter assay system that miR-200b inhibited ATAD2. BAY-850 significantly decreased the expression level of ATAD2 protein (p<0.05) and the proliferative capacity (p<0.05) but improved the apoptosis rate (p<0.05) of cells. Moreover, both miR-200b mimics and BAY-850 could distinctly repress the protein expression levels of PI3K and p-Akt of the PI3K/Akt signaling pathway (p<0.05) and enhance the expression of suppressor gene p53 (p<0.05).CONCLUSIONSMiR-200b-5p can inhibit the proliferation and promote the apoptosis of OC cells through targeted inhibition of ATAD2 expression and regulation of the PI3K/Akt signaling pathway.

17 Nov 2017·ACS Chemical BiologyQ2 · BIOLOGY

Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action

Q2 · BIOLOGY

Article

Author: Keefe, Anthony D. ; Holton, Simon J. ; Weiske, Joerg ; Troast, Dawn M. ; Huber, Kilian V. M. ; Zhang, Ying ; Bennett, James M. ; Puetter, Vera ; Gorjánácz, Mátyás ; Cuozzo, John W. ; Fernández-Montalván, Amaury E. ; Centrella, Paolo A. ; Díaz-Sáez, Laura ; Weinmann, Hilmar ; Berger, Markus ; Hübner, Jan ; Soutter, Holly H. ; Badock, Volker ; Clark, Matthew A. ; Dumelin, Christoph E. ; Roche, Didier ; Sigel, Eric A. ; Fedorov, Oleg ; Stöckigt, Detlef ; Hartung, Ingo V. ; Chaikuad, Apirat ; ter Laak, Antonius ; Rodeschini, Vincent ; Kuropka, Benno ; Koo, Seong Joo

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

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Neoplasms	Discovery	DE	Bayer AG	-

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