Hijacking the general transcription machinery by sequence specific transcription factors going awry

Introduction: The MiT family of transcription factors comprises four closely related members, MiTF, TFE3, TFEB and TFEC. All members of this family share a common structure, consisting of the helix-loop-helix leucine zipper dimerization motif, the transactivation domain and a DNA-binding domain that recognizes the consensus sequences (CA[T/C]GTG) called E-boxes. Due to the high homology between all MiT family members the unique function of each family member may therefore be dependent on its expression pattern and the different isoforms expressed in each tissue. Although their dysregulation by amplification, missense mutations, and translocations has been reported in many cancer types the underlying oncogenic mechanisms remain unclear.

Results: Our data reveal that the lineage-survival oncogene MITF controls the interface of nucleotide excision repair (NER) and transcription, an essential instrument to maintain genomic stability in eukaryotes, through transactivation of the general transcription factor 2H1 (GTF2H1), a TFIIH core element. In this way the NER/TFIIH complex is controlled in the presence and absence of UVR mediated genotoxic attack resulting in nucleotide repair deficiency and breakdown of global transcription upon MITF depletion. The association between MITF and GTF2H1 transcripts was confirmed by a transcriptome-wide comparative marker selection analysis in a panel of primary and metastatic melanomas based on high versus low MITF expression and TMA analyses of 140 primary cutaneous melanomas shows that expression of GTF2H1 is significantly linked to MITF abundance and was associated with prognostic melanoma stage. Moreover, RNA-interference mediated repression of GTF2H1 led to a significant reduction in tumor formation in a melanoma xenograft model and was associated with a significantly decrease of circulating tumor cells and lung metastases indicating that TFIIH plays an essential role in the spread of melanoma.

Conclusion: Collectively, these results describe an unanticipated role of MITF in the regulation of intimately linked NER and transcription machineries in the melanocytic lineage, which is preserved upon transformation into melanoma.

Mechanistically, deregulated transcriptional activity of MiT family members might elicit a deregulation of intimately linked NER and transcription machineries with potential implications for tumor initiation and progression. This has been observed before in cancer types such as clear cell sarcoma and renal carcinoma where translocations leading to aberrant expression of these transcription factors can single-handedly drive the oncogenic process. These findings may lead to discover novel opportunities to explore TFIIH-targeted intervention strategies.