ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE
Abstract 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 domai...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05993-9 |
| _version_ | 1827894819243950080 |
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| author | Praveen Guruvaiah Suresh Chava Chiao-Wang Sun Nirupama Singh Courtney A. Penn Romi Gupta |
| author_facet | Praveen Guruvaiah Suresh Chava Chiao-Wang Sun Nirupama Singh Courtney A. Penn Romi Gupta |
| author_sort | Praveen Guruvaiah |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T22:12:59Z |
| format | Article |
| id | doaj.art-65c81d8f41da468297d0844b5876e63c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T22:12:59Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-65c81d8f41da468297d0844b5876e63c2023-07-23T11:27:53ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711510.1038/s41419-023-05993-9ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPEPraveen Guruvaiah0Suresh Chava1Chiao-Wang Sun2Nirupama Singh3Courtney A. Penn4Romi Gupta5Department of Biochemistry and Molecular Genetics, The University of Alabama at BirminghamDepartment of Biochemistry and Molecular Genetics, The University of Alabama at BirminghamDepartment of Biochemistry and Molecular Genetics, The University of Alabama at BirminghamDepartment of Pathology, Division of Laboratory Medicine, University of Alabama at BirminghamDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Vanderbilt University Medical CenterDepartment of Biochemistry and Molecular Genetics, The University of Alabama at BirminghamAbstract 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.https://doi.org/10.1038/s41419-023-05993-9 |
| spellingShingle | Praveen Guruvaiah Suresh Chava Chiao-Wang Sun Nirupama Singh Courtney A. Penn Romi Gupta ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE Cell Death and Disease |
| title | ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE |
| title_full | ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE |
| title_fullStr | ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE |
| title_full_unstemmed | ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE |
| title_short | ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE |
| title_sort | atad2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating cenpe |
| url | https://doi.org/10.1038/s41419-023-05993-9 |
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