Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer.
Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer.
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Bcl-2相关转录因子1 Ser290磷酸化介导DNA损伤反应并调节胃癌的放射敏感性
DOI：
10.1186/s12967-021-03004-z
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发表时间：
2021-08-09
影响因子：
7.4
通讯作者：
Yang JH
中科院分区：
文献类型：
--
作者：
Liu J;Li J;Sun Z;Duan Y;Wang F;Wei G;Yang JH
DNA损伤反应在肿瘤发病和放疗抵抗中起着至关重要的作用。蛋白磷酸化是调控DNA损伤反应的重要机制；然而，胃癌放射敏感性的关键介质仍需进一步探索。采用高分辨率质谱法和开放式搜索方法对5例胃癌患者的配对肿瘤和邻近组织进行了快速无标记磷酸化蛋白质组学研究。利用基因集富集分析（Gene Set Enrichment Analysis， GSEA）对磷酸化蛋白进行鉴定并分析其相关通路。针对磷酸化位点的特异性抗体验证了主要受调控的磷酸化蛋白及其潜在功能。特异性蛋白磷酸化进一步通过功能和临床方法进行分析。共鉴定出832个胃癌相关独特磷酸化位点，其中上调25个，下调52个。值得注意的是，失调的磷酸化蛋白主要富集在dna损伤反应相关途径中。特别是bcl -2相关转录因子1 (BCLAF1) Ser290位点的磷酸化在肿瘤中显著上调。组织芯片研究证实BCLAF1 Ser290磷酸化（pBCLAF1 (Ser290)）在肿瘤中的上调，并进一步表明与胃癌患者预后不良相关。消除BCLAF1在Ser290位点的磷酸化抑制胃癌（GC）细胞的增殖。pBCLAF1 （Ser290）的上调与辐照诱导的细胞核中γ-H2AX的表达有关，导致DNA损伤修复反应增加，并明显抑制辐照诱导的癌细胞凋亡。BCLAF1 Ser290位点的磷酸化参与了DNA损伤反应的调控，是放疗耐药的重要靶点。在线版本包含补充材料，可在10.1186/s12967-021-03004-z获得。
DNA damage response plays critical roles in tumor pathogenesis and radiotherapy resistance. Protein phosphorylation is a critical mechanism in regulation of DNA damage response; however, the key mediators for radiosensitivity in gastric cancer still needs further exploration. A quick label-free phosphoproteomics using high-resolution mass spectrometry and an open search approach was applied to paired tumor and adjacent tissues from five patients with gastric cancer. The dysregulated phosphoproteins were identified and their associated-pathways analyzed using Gene Set Enrichment Analysis (GSEA). The mostly regulated phosphoproteins and their potential functions were validated by the specific antibodies against the phosphorylation sites. Specific protein phosphorylation was further analyzed by functional and clinical approaches. 832 gastric cancer-associated unique phosphorylated sites were identified, among which 25 were up- and 52 down-regulated. Markedly, the dysregulated phosphoproteins were primarily enriched in DNA-damage-response-associated pathways. Particularly, the phosphorylation of Bcl-2-associated transcription factor 1 (BCLAF1) at Ser290 was significantly upregulated in tumor. The upregulation of BCLAF1 Ser290 phosphorylation (pBCLAF1 (Ser290)) in tumor was confirmed by tissue microarray studies and further indicated in association with poor prognosis of gastric cancer patients. Eliminating the phosphorylation of BCLAF1 at Ser290 suppressed gastric cancer (GC) cell proliferation. Upregulation of pBCLAF1 (Ser290) was found in association with irradiation-induced γ-H2AX expression in the nucleus, leading to an increased DNA damage repair response, and a marked inhibition of irradiation-induced cancer cell apoptosis. The phosphorylation of BCLAF1 at Ser290 is involved in the regulation of DNA damage response, indicating an important target for the resistance of radiotherapy. The online version contains supplementary material available at 10.1186/s12967-021-03004-z.
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影响因子：
7.8
作者：
Chouchani, Edward T.;James, Andrew M.;Fearnley, Ian M.;Lilley, Kathryn S.;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
DOI：
10.1038/s41571-018-0114-z
发表时间：
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期刊：
Nature reviews. Clinical oncology
影响因子：
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影响因子：
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作者：
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影响因子：
7.4
作者：
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