Abstract:

The melanocyte-specific transcription factor MITF is an important gene essential for development, differentiation, and survival of melanocytes and plays an important role in melanoma. MITF is a member of the MiT family consisting of three other members, TFE3, TFEB, and TFEC. All MiT members contain a conserved domain, have the ability to homo- or hetero-dimerize, and can bind the same regulatory motif in target DNA highlighting a compensatory capacity. Recently the roles of the MiT family in oncogenesis have been expanded emphasizing multiple mechanisms of dysregulation in tumors. In particular, TFE3 and TFEB factors are involved in activating translocations in pediatric solid tumors while MITF is an amplified oncogene in metastatic melanoma and has been established as a direct downstream effector of the fusion oncoprotein EWS-ATF1.

This study used informatics approaches and molecular and biochemical techniques to examine melanomas with low MITF expression. As melanoma progresses, the expression of MITF decreases as detected by immunohistochemistry, a decrease correlated with poor prognosis, thus making these melanomas important to explore. New roles for TFE3 and TFEB in these melanomas and additionally TFEB in squamous cell carcinoma are established. This study demonstrates that overexpression of TFE3 is functionally important for the growth and proliferation of a subset of melanomas and oncogenic NFkB can transcriptionally regulate TFE3 contributing to its elevated expression. This study also establishes a new mechanism of dyregulation for TFEB through amplification and the amplified TFEB is necessary for the growth of melanoma and squamous cell carcinoma. Additionally, this study shows loss of SOX10, an upstream regulator of MITF, can contribute to MITF loss. Ectopic SOX10 expression can restore MITF expression which has implications for vaccine studies where MITF or MITF target antigen expression is often lost leading to relapse. The projects of this study combined help give new insight into the roles of the MiT family in melanoma, a role only attributed to MITF previously and it redefines the mechanism of action of the MiT family, particularly TFE3 and TFEB, where dysregulated expression can occur through a genetic lesion such as amplification or by elevated transcriptional regulation.