Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.
Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas.
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DOI：
10.1021/acs.jproteome.7b00405
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发表时间：
2017-10-06
影响因子：
4.4
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Thomas SN;Chen L;Liu Y;Höti N;Zhang H
大约20%的高级别浆液性卵巢癌是同源重组（HR）缺陷型，这是由于HR途径基因（包括肿瘤抑制基因BRCA 1和2）的遗传和表观遗传突变所致。HR缺陷（HRD）损害了细胞有效修复DNA损伤的能力，但也增加了对化疗治疗策略的敏感性;然而，并非所有患有HRD肿瘤的卵巢癌患者对化疗都表现出积极反应。我们先前基于iTRAQ的高级别浆液性卵巢癌的综合蛋白质组学表征发现，与非HRD肿瘤相比，HRD肿瘤与Lys 12和Lys 16（H4-K12 acK 16 ac）处的组蛋白H4乙酰化水平较低相关。在目前的研究中，我们开发并验证了一种基于H4-K12 acK 16 ac平行反应监测（PRM）的靶向质谱分析方法，以分析组蛋白H4的乙酰化变化，并确定这些变化与总H4，组蛋白乙酰转移酶和组蛋白脱乙酰酶（HDAC）水平的相关性。尽管H4和组蛋白乙酰转移酶的水平是稳定的，而与HRD状态无关，组蛋白H4乙酰化和一种HDAC（HDAC 6）的水平在HRD肿瘤中升高。还通过基于抗体的方法在另外的卵巢肿瘤中分析了相对H4乙酰化水平。与HRD相关的Lys 12和Lys 16处的特异性H4乙酰化可能为化疗治疗方式提供信息，以改善卵巢癌患者的治疗反应。
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.
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影响因子：
4.3
作者：
Liu FW;Tewari KS
通讯作者：
Tewari KS
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
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Cancer Genome Atlas Research Network
影响因子：
28.2
作者：
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通讯作者：
Clinical Proteomic Tumor Analysis Consortium (CPTAC)
影响因子：
5.3
作者：
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通讯作者：
Akhtar, A