Constitutive and IFNγ-induced activation of MHC2TA promoter type III in human melanoma cell lines is governed by separate regulatory elements within the PIII upstream regulatory region

Cell lines established from tumor tissue of cutaneous melanoma biopsies often display constitutive and IFNγ-inducible expression of MHC class II molecules. The expression of MHC class II molecules in melanoma is associated with an overall poor prognosis and unfavorable clinical outcome. We have analyzed the DNA elements and interacting transcription factors that control the constitutive and IFNγ-inducible expression of the class II transactivator (CIITA), a co-activator essential for transcription of all MHC class II genes. Our studies reveal the activation of multiple CIITA promoter regions (CIITA-PII, -PIII and -PIV) in melanoma cell lines for both the constitutive and IFNγ-inducible expression of MHC class II molecules. Furthermore, we show that constitutive and IFNγ-inducible expression of the CIITA-PIII isoform is governed by separate regulatory elements within the PIII upstream regulatory region (PURR). Similarly constitutive activation in melanoma of CIITA-PII, CIITA-PIII, and CIITA-PIV does not require components of the IFNγ signaling pathway. However, these components are readily recruited to the PURR and CIITA-PIV after exposure of cells to IFNγ and account for the IFNγ-induced expression of CIITA. Together, our data reveal the contribution of distinct elements and factors in the constitutive and IFNγ-inducible expression of CIITA in melanoma cell lines of the skin.