The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers.
The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers.
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DOI：
10.1158/0008-5472.can-15-2171-t
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发表时间：
2015-11-01
期刊：
影响因子：
11.2
通讯作者：
Harris RS
中科院分区：
文献类型：
--
作者：
Leonard B;McCann JL;Starrett GJ;Kosyakovsky L;Luengas EM;Molan AM;Burns MB;McDougle RM;Parker PJ;Brown WL;Harris RS
抗病毒DNA胞嘧啶脱氨酶APOBEC3B的过表达与许多癌症的体细胞突变有关。HPV感染导致宫颈癌和头颈癌中APOBEC3B表达上调，但非病毒性恶性肿瘤的机制尚不清楚。在这项研究中，我们研究了APOBEC3B上调的信号转导途径。二酰基甘油（DAG）模拟苯酚-肉豆蔻酸（PMA）激活蛋白激酶C （PKC）导致APOBEC3B表达和活性特异性和剂量反应性增加，然后PKC或NFκB抑制可强烈抑制APOBEC3B表达和活性。PKC激活导致RELB募集到APOBEC3B启动子，而不是RELA募集到非典型NFκB信号通路。值得注意的是，在多种肿瘤类型的癌细胞系中，APOBEC3B的上调需要PKC。通过揭示APOBEC3B如何在许多癌症中上调，我们的研究结果表明PKC和NFκB抑制剂可能被重新定位以抑制癌症突变，抑制肿瘤进化，并降低耐药和转移等不良结局的可能性。
Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. HPV infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying non-viral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol (DAG) mimic phorbol-myristic acid (PMA) resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NFκB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter implicating non-canonical NFκB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NFκB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases.