Functional role of PRDM7 in melanoma and its regulation by MITF

BMC Seminar Thursday 7nd of April at 12:00 on Zoom.

Speaker: Vu Hong Nhung, Doctoral student under the supervision of Prof. Eiríkur Steingrímsson, Faculty of Medicine, Department of Biomedical Science, School of Health Science, University of Iceland.

Title: Functional role of PRDM7 in melanoma and its regulation by MITF

Abstract: Microphthalmia-associated transcription factor (MITF) is known as an essential regulator of melanocyte specification, melanoma cell proliferation, invasion, and drug resistance. The major changes in gene expression upon MITF loss suggest that it might be involved in regulating epigenetic modifiers to reshape the melanoma chromatin state. By searching for epigenetic modifiers that depend on MITF expression, the histone methyltransferase PRDM7 was observed to be significantly reduced upon MITF knockout and increased upon MITF overexpression. Interestingly, PRDM7 is primate-specific and analysis of all tumours in the TCGA shows that it is primarily expressed in melanomas. To date, however, the biological role of PRDM7 remains uncharacterized. We have used knockout and knockdown studies to characterise the functional roles of PRDM7 in melanoma. Although the depletion of PRDM7 did not affect the expression of the MITF mRNA, MITF protein expression was significantly reduced in PRDM7-KO and KD cells, suggesting that PRDM7 affects protein stability or expression. PRDM7-KO cells proliferated slowly and their morphology and cytoskeletal structure were altered compared to the control cells.

Similar changes were observed upon MITF knockdown. Consistent with this, RNA-sequencing showed that the PRDM7-KO cells were enriched for genes involved in the extracellular matrix and structural organisation as well as with EMT genes signature.  The same pathways were also enriched upon MITF knockouts and knockdowns, suggesting that MITF mediated repression, at least partially, through PRDM7. Interestingly, the depletion of either MITF or PRDM7 leads to a massive change in the repressive histone marks H3K9me3 and H3K27me3 in melanoma cells. Our results suggest that MITF and PRDM7 regulate each other’s expression and are involved in reshaping the chromatin state in melanoma.