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Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.

ABSTRACT: Approximately 20% of high-grade serous ovarian cancers are homologous-recombination (HR)-deficient due to genetic and epigenetic mutations of HR pathway genes including the tumor suppressor genes BRCA1 and 2. HR deficiency (HRD) compromises cells' ability to efficiently repair DNA damage, but it also increases sensitivity to chemotherapeutic treatment strategies; however, not all ovarian cancer patients with HRD tumors exhibit positive responses to chemotherapy. Our previous iTRAQ-based comprehensive proteomic characterization of high-grade serous ovarian carcinomas found that lower levels of histone H4 acetylation at Lys12 and Lys16 (H4-K12acK16ac) were associated with HRD tumors compared with non-HRD tumors. In the current study, we developed and validated an H4-K12acK16ac parallel-reaction-monitoring (PRM)-targeted mass-spectrometry-based assay to analyze acetylation changes of histone H4 and to determine the association of these changes with total H4, histone acetyltransferase, and histone deacetylase (HDAC) levels. Whereas the levels of H4 and histone acetyltransferases were stable irrespective of HRD status, the levels of histone H4 acetylation and one HDAC, HDAC6, were elevated in the HRD tumors. Relative H4 acetylation levels were also analyzed by an antibody-based approach in additional ovarian tumors. It is possible that specific H4 acetylation at Lys12 and Lys16 associated with HRD could inform chemotherapeutic treatment modalities to improve ovarian cancer patients' treatment response.

SUBMITTER: Thomas SN

PROVIDER: S-EPMC5630524 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.

Thomas Stefani N SN Chen Lijun L Liu Yang Y Höti Naseruddin N Zhang Hui H

Journal of proteome research 20170914 10

Approximately 20% of high-grade serous ovarian cancers are homologous-recombination (HR)-deficient due to genetic and epigenetic mutations of HR pathway genes including the tumor suppressor genes BRCA1 and 2. HR deficiency (HRD) compromises cells' ability to efficiently repair DNA damage, but it also increases sensitivity to chemotherapeutic treatment strategies; however, not all ovarian cancer patients with HRD tumors exhibit positive responses to chemotherapy. Our previous iTRAQ-based comprehe ...[more]

PMID: 28866885

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Project description:BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Dataset Information

Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.

Publications

Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.

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