Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress
Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress
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DOI：
10.2353/ajpath.2009.090091
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发表时间：
2009-10-01
影响因子：
6
通讯作者：
Teitell, Michael A.
中科院分区：
文献类型：
--
作者：
Balatoni, Cynthia E.;Dawson, David W.;Teitell, Michael A.
B细胞淋巴瘤是人类最常见的免疫系统恶性肿瘤，通常含有TCL1癌基因表达异常。TCL1转基因(TCL1-TG)小鼠发生一系列B细胞恶性肿瘤，支持TCL1在B细胞中的致癌作用。我们先前对TCL1-TG B细胞淋巴瘤DNA甲基化模式的全球调查发现了许多淋巴瘤特异的候选高甲基化基因，包括Stk39。Stk39编码的蛋白，不育的20-like相关的富含Pro的丙氨酸激酶(SPAK)，调节细胞应激反应，微阵列研究发现Spak在转移性前列腺癌和耐药乳腺癌中表达降低，表明它的缺失可能在癌症的进展中起作用。在这里，我们在TCL1-TG B细胞淋巴瘤中发现了DNA高甲基化和SPAK沉默，在多个亚型的人类B细胞淋巴瘤中发现了没有DNA甲基化的SPAK沉默。Spak被shRNA敲除可以保护B细胞免受DNA双链断裂诱导的caspase依赖的细胞凋亡，但不能保护渗透或氧化细胞应激源诱导的细胞凋亡。在DNA损伤的B细胞中，通过Spak抑制caspase3的裂解激活是受损的。有趣的是，c-jun氨基末端激酶可能被SPAK激活，而在表达SPAK的B细胞中对c-Jun氨基末端激酶的药理抑制概括了SPAK基因敲除的细胞保护表型。综上所述，这些数据表明，B细胞淋巴瘤中的SPAK缺失促进了DNA损伤导致的细胞存活率增加，并为增强癌症对遗传毒性应激的抵抗力提供了一种潜在的机制。(Am J Pathol 2009175：1653-1661；DOI：10.2353/ajpath.2009.090091)
B-cell lymphomas, the most frequent human immune system malignancies, often contain dysregulated TCL1 oncogene expression. TCL1 transgenic (TCL1-tg) mice develop a spectrum of B-cell malignancies, supporting an oncogenic role for TCL1 in B cells. Our prior global survey of DNA methylation patterns in TCL1-tg B-cell lymphomas identified many lymphoma-specific candidate hypermethylated genes, including Stk39. The Stk39 encoded protein, sterile 20-like-related proline-alanine-rich kinase (SPAK), regulates cell stress responses, and microarray studies identified reduced SPAK expression in metastatic prostate and treatment-resistant breast cancers, suggesting that its loss may have a role in cancer progression. Here we identified DNA hypermethylation and SPAK silencing in TCL1-tg B-cell lymphomas and SPAK silencing without DNA methylation in multiple subtypes of human B-cell lymphomas. SPAK knockdown by shRNA protected B cells from caspase-dependent apoptosis induced by DNA double-strand breaks but not apoptosis in response to osmotic or oxidative cell stressors. Caspase 3 activation by cleavage was impaired with SPAK repression in DNA damaged B cells. Interestingly, c-Jun NH2-terminal kinase is potentially activated by SPAK and pharmacological inhibition of c-Jun NH2-terminal kinase in SPAK-expressing B cells recapitulated the cell-protective phenotype of SPAK knockdown. Taken together, these data indicate that SPAK loss in B-cell lymphomas promotes in-creased cell survival with DNA damage and provides a potential mechanism for increased resistance to genotoxic stress in cancer. (Am J Pathol 2009, 175:1653-1661; DOI: 10.2353/ajpath.2009.090091)