MLL4 mediates differentiation and tumor suppression through ferroptosis

Menée in vitro et à l'aide de modèles murins de carcinome épidermoïde, cette étude met en évidence un mécanisme par lequel le régulateur épigénétique MLL4, via la ferroptose, favorise la différenciation épidermique et la suppression tumorale

Résumé en anglais

The epigenetic regulator, MLL4 (KMT2D), has been described as an essential gene in both humans and mice. In addition, it is one of the most commonly mutated genes in all of cancer biology. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression. Mice lacking epidermal Mll4, but not the related enzyme Mll3 (Kmt2c), display features of impaired differentiation and human precancerous neoplasms, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, and Aloxe3). Beyond revealing a new mechanistic basis for Mll4-mediated tumor suppression, our data uncover a potentially much broader and general role for ferroptosis in the process of differentiation and skin homeostasis.