MLL4 mediates differentiation and tumor suppression through ferroptosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34890228.
- Also identified by DOI 10.1126/sciadv.abj9141 and PMC identifier 8664260.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The epigenetic regulator, <i>MLL4</i> (<i>KMT2D</i>), 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 <i>Mll4</i>, but not the related enzyme <i>Mll3</i> (<i>Kmt2c</i>), 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 (<i>Alox12</i>, <i>Alox12b</i>, and <i>Aloxe3</i>). Beyond revealing a new mechanistic basis for <i>Mll4</i>-mediated tumor suppression, our data uncover a potentially much broader and general role for ferroptosis in the process of differentiation and skin homeostasis.