Abstract
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.
Highlights
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
transcription factor II A (TFIIA) was initially described as a nuclear transcriptional regulator[37], we identified a significant fraction of TFIIA accumulating to the cytoplasm due to a highly efficient nuclear export signal
To identify genes differentially expressed in HNSCC primary tumours (PT) versus lymph node metastasis (M) and the corresponding non-malignant tissue (N), tissues were obtained from 20 patients undergoing surgical resection
Summary
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 prevailing form of HNC, head and neck squamous cell carcinoma (HNSCC), is characterized as a very aggressive and invasive cancer type affecting multiple sites of the upper aerodigestive tract like the nasal cavity, mouth, salivary glands, larynx and pharynx[2,3]. TFIIAαβ is posttranslationally processed by Taspase[1] at an evolutionary conserved cleavage site QVDG (aa 272 to 275)[23] Both uncleaved αβ and the cleaved α- and β-subunits can be found in association with the TFIIAγ subunit in vivo[26,27]. The observation that cleavage is the prerequisite for proteasome mediated degradation of TFIIA28 indicates that cleavage regulates TFIIA stability and transcriptional activity This hypothesis was supported by a study showing that Taspase1-mediated cleavage of TFIIA ensures proper head formation during mouse development[18]. The tumour suppressor p16INK4a is in focus of interest as putative biomarker for HNSCC
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