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The bromodomain protein TRIM28 controls the balance between growth and invasiveness in melanoma

ABSTRACT: Melanoma tumors are highly metastatic partly due to the ability of melanoma cells to transition between invasive and proliferative states, however, the mechanisms underlying this plasticity are still not fully understood. To identify new epigenetic regulators of melanoma plasticity, we combined data mining, tumor models, proximity proteomics, and CUT&RUN-sequencing. We focused on the druggable family of bromodomain epigenetic readers, and identified TRIM28 as a new regulator of melanoma plasticity. We found that TRIM28 promotes the expression of pro-invasive genes, and that TRIM28 controls the balance between invasiveness and growth of melanoma cells. We demonstrate that TRIM28 acts via the transcription factor JUNB, that directly regulates the expression of pro-invasive and pro-growth genes. Mechanistically, TRIM28 controls the expression of JUNB by negatively regulating its transcriptional elongation by RNA polymerase II. In conclusion, our results demonstrate that a TRIM28-JUNB axis controls the balance between invasiveness and growth in melanoma tumors and suggests that the bromodomain protein TRIM28 could be targeted to reduce tumor spread.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210579 | GEO | 2022/08/08

REPOSITORIES: GEO

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Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.

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The bromodomain protein TRIM28 controls the balance between growth and invasiveness in melanoma

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