We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma.
The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
Among the SKI targets were microphthalmia-associated transcription factor and Nr-CAM, two proteins associated with melanoma cell survival, growth, motility, and transformation.
Collectively, these data indicate that CDK2 activity in melanoma is largely maintained at the transcriptional level by MITF, and unlike other malignancies, it may be a suitable drug target in melanoma.
These data suggest that MITF is an anti-proliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF.
Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm.
Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2).
Melanocyte-stimulating hormone-induced expression of MITF protein caused increased sensitivity to 4-TBP, whereas sensitivity of melanomas correlated with MITF expression.
Using an integrated analysis of high-resolution single nucleotide polymorphism maps and gene expression databases associated with the NCI60 collection cancer cell lines, we identified the transcription factor MITF as an amplified oncogene in melanoma that is critical for anchoring lineage dependence and malignant character.
We show that EWS-ATF1 occupies the MITF promoter, mimicking melanocyte-stimulating hormone (MSH) signaling to induce expression of MITF, the melanocytic master transcription factor and an amplified oncogene in melanoma.
For example, MITF (microphthalmia-associated transcription factor), which is a master regulator of the melanocyte lineage, might become a melanoma oncogene when deregulated in certain genetic contexts.
It has been demonstrated that MITF is an amplified oncogene in a fraction of human melanomas and that it also has an oncogenic role in human clear cell sarcoma.
By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery.
This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype.
Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response.
Microphthalmia-associated transcription factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas.