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.