Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany.
Scientific Computing and Bioinformatics, Johannes Gutenberg University, Staudingerweg 9, Mainz, 55128, Germany.
Sci Rep. 2017 Nov 2;7(1):14937. doi: 10.1038/s41598-017-14814-x.
Head and neck cancer (HNC) is the seventh most common malignancy in the world and its prevailing form, the head and neck squamous cell carcinoma (HNSCC), is characterized as aggressive and invasive cancer type. The transcription factor II A (TFIIA), initially described as general regulator of RNA polymerase II-dependent transcription, is part of complex transcriptional networks also controlling mammalian head morphogenesis. Posttranslational cleavage of the TFIIA precursor by the oncologically relevant protease Taspase1 is crucial in this process. In contrast, the relevance of Taspase1-mediated TFIIA cleavage during oncogenesis of HNSCC is not characterized yet. Here, we performed genome-wide expression profiling of HNSCC which revealed significant downregulation of the TFIIA downstream target CDKN2A. To identify potential regulatory mechanisms of TFIIA on cellular level, we characterized nuclear-cytoplasmic transport and Taspase1-mediated cleavage of TFIIA variants. Unexpectedly, we identified an evolutionary conserved nuclear export signal (NES) counteracting nuclear localization and thus, transcriptional activity of TFIIA. Notably, proteolytic processing of TFIIA by Taspase1 was found to mask the NES, thereby promoting nuclear localization and transcriptional activation of TFIIA target genes, such as CDKN2A. Collectively, we here describe a hitherto unknown mechanism how cellular localization and Taspase1 cleavage fine-tunes transcriptional activity of TFIIA in HNSCC.
头颈部癌症（HNC）是世界上第七种最常见的恶性肿瘤，其主要形式是头颈部鳞状细胞癌（HNSCC），其特点是侵袭性和侵袭性癌症。转录因子 II A（TFIIA）最初被描述为 RNA 聚合酶 II 依赖性转录的一般调节因子，是控制哺乳动物头发生长的复杂转录网络的一部分。肿瘤相关蛋白酶 Taspase1 对 TFIIA 前体的翻译后切割在这个过程中至关重要。相比之下，Taspase1 介导的 TFIIA 切割在 HNSCC 发生中的相关性尚未得到表征。在这里，我们对 HNSCC 进行了全基因组表达谱分析，结果显示 TFIIA 的下游靶标 CDKN2A 显著下调。为了在细胞水平上确定 TFIIA 的潜在调节机制，我们对 TFIIA 变体的核质转运和 Taspase1 介导的切割进行了表征。出乎意料的是，我们鉴定出一个进化保守的核输出信号（NES），该信号拮抗核定位，从而抑制 TFIIA 的转录活性。值得注意的是，Taspase1 对 TFIIA 的蛋白水解处理被发现掩盖了 NES，从而促进了 TFIIA 靶基因（如 CDKN2A）的核定位和转录激活。总的来说，我们在这里描述了一种以前未知的机制，即细胞定位和 Taspase1 切割如何精细调节 HNSCC 中 TFIIA 的转录活性。
