IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.
IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.
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DOI：
10.18632/oncotarget.6028
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发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
Wells SI
中科院分区：
文献类型：
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作者：
Adams AK;Bolanos LC;Dexheimer PJ;Karns RA;Aronow BJ;Komurov K;Jegga AG;Casper KA;Patil YJ;Wilson KM;Starczynowski DT;Wells SI
染色质结合的DEK蛋白最近被报道促进HPV+和HPV−头颈部鳞状细胞癌的生长。在HNSCC中，DEK调控的相关细胞和分子机制(S)仍然知之甚少。虽然已知DEK调节特定的转录靶点，但HNSCC中依赖于DEK的全球基因网络尚不清楚。为了确定DEK的转录特征，我们对DEK熟练或缺乏的HNSCC细胞进行了RNA测序(RNA-Seq)。生物信息学分析和随后的验证表明，炎症信号调节因子IRAK1和依赖于IRAK1的调控网络在HNSCC的DEK基因敲除后受到显著抑制。根据TCGA数据，14%的HNSCC标本过度表达IRAK1，从而支持可能的致癌功能。此外，在HNSCC细胞系中，IRAK1的基因或药物抑制足以减弱ERK1/2等下游信号，并通过凋亡诱导HNSCC细胞死亡。最后，与单独靶向相比，同时靶向DEK和IRAK1可促进细胞死亡。我们的发现表明，IRAK1促进了细胞的存活，是HNSCC细胞的一个有吸引力的治疗靶点。因此，我们提出了一个模型，在该模型中，IRAK1独立地和DEK一起刺激肿瘤信号和表型。
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.