FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis
FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis
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FOXA1 拮抗 EZH2 介导的 CDKN2A 致癌作用抑制
DOI：
10.1016/j.bbrc.2014.09.092
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发表时间：
2014-10-10
影响因子：
3.1
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Zhang, Yu;Tong, Tanjun
CDKN 2A（p16（INK 4a））是参与许多癌症的重要肿瘤抑制因子。我们最近的研究表明，FOXA 1作为一个叉头转录因子介导的细胞衰老中的CDKN 2A激活。然而，这一轴在致癌作用中的作用仍不清楚。在这里，使用全面收集的癌症微阵列数据，我们发现FOXA 1在许多癌症中与其正常对应物相比下调，并且FOXA 1和CDKN 2A之间的正相关性可以在具有较低EZH 2（CDKN 2A的表观遗传阻遏物）表达的前列腺癌和乳腺癌中观察到。在实验上，前列腺癌和乳腺癌细胞中的上位性分析表明，FOXA 1的更高表达对抗EZH 2介导的CDKN 2A抑制，因为FOXA 1的进一步消耗逆转了由EZH 2抑制引起的CDKN 2A的去沉默。同时，EZH 2消耗抑制癌细胞周期进展，并且这种调节在FOXA 1和CDKN 2A存在下得到优化。进一步的致癌转化试验表明，EZH 2的过表达不足以阻断RAS诱导的CDKN 2A活化，而FOXA 1的缺失是增强EZH 2介导的CDKN 2A沉默和绕过衰老屏障的必要条件。重要的是，使用体外组蛋白甲基转移酶（HMTase）系统，我们发现FOXA 1通过其C-末端组蛋白结合基序直接抑制EZH 2的组蛋白甲基转移酶活性。这些数据支持FOXA 1对CDKN 2A的正性调节抵消了癌症中EZH 2对CDKN 2A的致瘤性抑制。(C)2014 Elsevier Inc. All rights reserved.
CDKN2A (p16(INK4a)) is a crucial tumor suppressor involved in many cancers. Our recent investigations revealed that FOXA1 as a forkhead transcription factor mediates CDKN2A activation in cellular senescence. However, the contribution of this axis in carcinogenesis remains unclear. Here, using a comprehensive collection of cancer microarray data, we found FOXA1 is down-regulated in many cancers compared to their normal counterparts and the positive correlation between FOXA1 and CDKN2A could be observed in prostate and breast cancers with lower EZH2 (epigenetic repressor for CDKN2A) expression. Experimentally, epistasis analysis in prostate and breast cancer cells indicated that higher expression of FOXA1 opposes EZH2-mediated CDKN2A repression, as further depletion of FOXA1 reverts the de-silencing of CDKN2A caused by EZH2 inhibition. Concomitantly, EZH2-depletion suppresses cancer cell cycle progression and this regulation is optimized in the presence of FOXA1 and CDKN2A. A further oncogenic transformation assay suggested that overexpression of EZH2 is insufficient to block RAS-induced CDKN2A activation and loss of FOXA1 is mandatory to potentiate EZH2-mediated CDKN2A silencing and to bypass the senescence barrier. Importantly, using an in vitro histone methyltransferase (HMTase) system, we found FOXA1 directly inhibits EZH2's histone methyltransferase activity through its C-terminal histone binding motif. These data support that positive regulation of CDKN2A by FOXA1 counteracts its tumorigenic repression of by EZH2 in cancers. (C) 2014 Elsevier Inc. All rights reserved.