MEN1 deficiency creates a selenite-dependent switch in ferroptosis
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Ronnie Ren Jie Low Venkata Nishita Mohan Parnandi Aurora Idilli Ersa Gjelaj Fernanda Teixeira Subtil Sandra Segura-Bayona James MacRae Simon BoultonThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
Replication stress is a driver of cancer cell death, yet how genetic and environmental factors impact cellular tolerance remains unclear. Here, we identify the loss of the chromatin scaffold MEN1 as a determinant of replication stress resistance and show that this phenotype arises from suppression of ferroptosis. MEN1-deficient cells exhibit reduced expression of ACSL1 and SLC7A11, creating an intrinsic ferroptosis-sensitized state. Unexpectedly, this vulnerability is masked by environmental selenium, which drives GPX4 upregulation independently of SLC7A11. As a result, MEN1 deficiency establishes a selenium-dependent binary switch between ferroptosis hypersensitivity and resistance, which dictates cellular responses to replication stress. Mechanistically, this state is regulated by an H3.3-dependent transcriptional program linking chromatin remodeling to lipid and redox metabolism. These findings reveal that micronutrient availability can override genetically encoded cell-death programs and uncover a context-dependent vulnerability in MEN1 mutant cancers.
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bioRxiv
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