STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway

Abstract

Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRAS Q61K in an Ink4a deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain and liver metastases. Whole genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.

Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR

“…Interestingly, transcriptome analysis revealed upregulation of Stat1 mRNA levels in OP9 and increased expression of Stat3 and Stat5 in NIH/3T3 cells. Active STAT3 and STAT5 signaling are known to increase proliferation in different cellular contexts [68][69][70][71], while STAT1 mainly acts as an antiproliferative factor [72][73][74]. Induction of proliferation in response to huOSM was also demonstrated to be related to STAT3 activation [47], whereas growth-inhibitory effects of huOSM have been found to be mediated by JAK3 and STAT1 activation [41].…”

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas

“…IL6 is a classic inducer of STAT3 and induces inflammatory processes. STAT3 was shown to repress MITF and reduces the proliferation of melanoma cells [ 29 ].…”

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor

“…Moreover, their biology might differ substantially from the primary tumor 70 . For instance, STAT3 favors the spread of melanoma cells to distant organs, and it is particularly expressed in the melanoma metastasis 53,54 . For this reason, the identification of the IL-1α -STAT3 axis, able to address efficiently metastases at their first stage, gains particular clinical relevance 48,71 .…”

“…5C). This gene codifies for the transcription factor STAT3, a well characterized mediator of aggressiveness in different cancers, including melanoma 53,54 . Furthermore, scSeq analysis of STAT3 expression highlighted the metastatic melanoma as the cells exhibiting the highest expression levels of this transcription factor (Fig.…”