Abstract
The transcription factor ATF2 has been shown to attenuate melanoma susceptibility to apoptosis and to promote its ability to form tumors in xenograft models. To directly assess ATF2's role in melanoma development, we crossed a mouse melanoma model (NrasQ61K::Ink4a−/−) with mice expressing a transcriptionally inactive form of ATF2 in melanocytes. In contrast to 7/21 of the NrasQ61K::Ink4a−/− mice, only 1/21 mice expressing mutant ATF2 in melanocytes developed melanoma. Gene expression profiling identified higher MITF expression in primary melanocytes expressing transcriptionally inactive ATF2. MITF downregulation by ATF2 was confirmed in the skin of Atf2−/− mice, in primary human melanocytes, and in 50% of human melanoma cell lines. Inhibition of MITF transcription by MITF was shown to be mediated by ATF2-JunB–dependent suppression of SOX10 transcription. Remarkably, oncogenic BRAF (V600E)–dependent focus formation of melanocytes on soft agar was inhibited by ATF2 knockdown and partially rescued upon shMITF co-expression. On melanoma tissue microarrays, a high nuclear ATF2 to MITF ratio in primary specimens was associated with metastatic disease and poor prognosis. Our findings establish the importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression.
Highlights
Malignant melanoma is one of the most highly invasive and metastatic tumors [1], and its incidence has been increasing at a higher rate than other cancers in recent years [2]
Recent studies indicate a role for microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and biogenesis, in melanoma progression
We demonstrate that the transcription factor Activating transcription factor 2 (ATF2) negatively regulates MITF transcription in melanocytes and in about 50% of melanoma cell lines
Summary
Malignant melanoma is one of the most highly invasive and metastatic tumors [1], and its incidence has been increasing at a higher rate than other cancers in recent years [2]. Significant advances in understanding melanoma biology have been made over the past few years, thanks to identification of genetic changes along the MAPK signaling pathway. Those include mutations in BRAF, NRAS, KIT and GNAQ, all of which result in a constitutively active MAPK pathway [3,4,5]. Constitutively active MAPK/ERK causes rewiring of other signaling pathways [4]. Among examples of rewired signaling is upregulation of C-JUN expression and activity [8], which potentiates other pathways, including PDK1, AKT and PKC, and plays a critical role in melanoma development [12]
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