FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma.
FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma.
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DOI：
10.1038/leu.2014.126
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发表时间：
2014-12
期刊：
影响因子：
11.4
通讯作者：
Samaniego F
中科院分区：
文献类型：
--
作者：
Sehgal L;Mathur R;Braun FK;Wise JF;Berkova Z;Neelapu S;Kwak LW;Samaniego F
fas介导的细胞凋亡受损与不良的临床结果和癌症化疗耐药有关。可溶性Fas受体（sFas receptor, sFas）是由外显子6的跳变产生的，通过分离Fas配体抑制细胞凋亡。血清sFas与非霍奇金淋巴瘤预后不良相关。我们发现淋巴瘤中Fas的选择性剪接受到Fas反义转录物（Fas - as1）对应的lncRNA的严格调控。FAS-AS1的水平与sFas的产生呈负相关，并且与RBM5结合的FAS-AS1抑制RBM5介导的外显子6跳变。EZH2在淋巴瘤中经常发生突变或过表达，它使FAS-AS1启动子超甲基化并抑制FAS-AS1的表达。ezh2介导的FAS-AS1启动子抑制可以通过DZNeP释放，也可以通过FAS-AS1的异位表达来克服，这两种方式都会增加FAS-AS1的水平，并相应降低fas的表达。布鲁顿酪氨酸激酶（BTK）抑制剂或EZH2敲低治疗可降低EZH2、RBM5和sfa的水平，从而增强fas介导的细胞凋亡。这是首次报道Fas的反义RNA对Fas抑制的功能调控。我们的研究结果揭示了淋巴瘤的新治疗靶点，并为EZH2抑制剂或依鲁替尼与招募Fas的化疗药物联合使用提供了理论依据，以有效杀死细胞。
Impaired Fas-mediated apoptosis is associated with poor clinical outcomes and cancer chemoresistance. Soluble Fas receptor (sFas), produced by skipping of exon 6, inhibits apoptosis by sequestering Fas ligand. Serum sFas is associated with poor prognosis of non-Hodgkin's lymphomas. We found that the alternative splicing of Fas in lymphomas is tightly regulated by a lncRNA corresponding to an antisense transcript of Fas (FAS-AS1). Levels of FAS-AS1 correlate inversely with production of sFas and FAS-AS1 binding to the RBM5 inhibits RBM5-mediated exon 6 skipping. EZH2, often mutated or overexpressed in lymphomas, hyper-methylates the FAS-AS1 promoter and represses the FAS-AS1 expression. EZH2-mediated repression of FAS-AS1 promoter can be released by DZNeP or overcome by ectopic expression of FAS-AS1, both of which increase levels of FAS-AS1 and correspondingly decrease expression of sFas. Treatment with Bruton’s tyrosine kinase (BTK) inhibitor or EZH2 knockdown decreases the levels of EZH2, RBM5 and sFas thereby enhances Fas-mediated apoptosis. This is the first report showing functional regulation of Fas repression by its antisense RNA. Our results reveal new therapeutic targets in lymphomas and provide a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing.
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影响因子：
10.3
作者：
Berkova, Zuzana;Wang, Shu;Samaniego, Felipe
通讯作者：
Samaniego, Felipe
影响因子：
11.5
作者：
Chase, Andrew;Cross, Nicholas C. P.
通讯作者：
Cross, Nicholas C. P.
影响因子：
4
作者：
Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
12.4
作者：
Friesen, C;Fulda, S;Debatin, KM
通讯作者：
Debatin, KM
DOI：
10.1016/j.lab.2005.05.004
发表时间：
2005-09-01
期刊：
JOURNAL OF LABORATORY AND CLINICAL MEDICINE
影响因子：
--
作者：
Aratake, K;Kamachi, M;Eguchi, K
通讯作者：
Eguchi, K