KDM6A is a lysine demethylase with well characterised roles in tumour suppression. Interestingly, this X-linked gene fails to undergo inactivation of the second gene copy in females, potentially contributing to the female survival advantage observed in many cancers including melanoma.
Here we show that KDM6A is more highly expressed in female melanomas and is associated with increased tumour infiltrating lymphocytes, decreased melanoma cell proliferation and better overall survival compared to males. Melanomas from male patients who have relapsed on BRAF inhibitor treatment show a striking loss of KDM6A compared to females. Functional studies using CRISPR-Cas9 depletion of KDM6A caused increased cell proliferation and colony formation, consistent with a tumour suppressive role. RNAseq identified target genes and revealed that female melanoma cell lines were more transcriptionally responsive compared to males.
As tumour suppressor genes are difficult to target therapeutically, we explored whether depletion of KDM6A may sensitise melanoma cells to other epigenetic inhibitors, as reported previously in several other cancers. This was indeed the case for several drugs targeting EZH2, BET proteins and HDACs
We next compared and contrasted the effects of GSK-J4, a pan KDM6 family inhibitor. In contrast to KDM6A knockdown, GSK-J4 lead to significant decreases in melanoma colony formation and increased apoptosis in 2D cultures and 3D spheroids. This is most likely due to the drugs ability to target KDM6B, a paralogue of KDM6A reported to have oncogenic properties in melanoma, that we found to be upregulated following KDM6A loss in a compensatory manner.
Collectively our results support a tumour suppressive role for KDM6A in melanoma, that is particularly prominent in women compared to men. Male melanoma patients with low KDM6A expression may respond well to drugs that target other epigenetic regulators, or specific inhibitors of KDM6B. Understanding these subtleties will improve outcomes for both sexes.