MLL4 mediates differentiation and tumor suppression through ferroptosis

Egolf, Shaun; Zou, Jonathan; Anderson, A.; Simpson, Cory L.; Aubert, Yann; Prouty, Stephen M.; Ge, Kai; Seykora, John T.; Capell, Brian C.

doi:10.1126/sciadv.abj9141

Cited by 45 publications

(41 citation statements)

References 58 publications

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“…We speculated that some of the epigenetic factors may possess essential roles in the regulation of both tumor aggressive behaviors and tumor immunity, and thus can favor both tumor development and suppression. In accordance with our assumption, prior studies have found conditional deletion of Mll4 confers growth advantages and causes blockade of differentiation program and ferroptosis suppression, thus synergizing with genetic lesions of additional genes to promote tumor development in multiple mouse tissues 34 , 35 , 55 , 73 , 74 . We and others found that Mll4 ablation elevates the expression of multiple chemokines, including CXCL9 and CXCL10, and the increased levels of molecules responsible for antigen processing and presentation 75 , which augments CD8 + T-cell-mediated anti-tumor immune response to suppress tumor development 16 , 49 .…”

Section: Discussionsupporting

confidence: 90%

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

et al. 2022

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Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.

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Section: Discussionsupporting

confidence: 90%

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

et al. 2022

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“…This variant causes GSH and CoA accumulation (Leu et al, 2019), as well as iron accumulation and increased risk of infection, but resistance to the malaria toxin hemozoin, perhaps explaining its selection in regions with a high risk for malarial infection (Singh et al, 2020). Knockout in mice of the epigenetic regulator MLL4, which is commonly altered in cutaneous squamous cell carcinomas in the skin, caused the development of pre-cancerous skin lesions (Egolf et al, 2021). The loss of MLL4 in the skin of these mice drives transcriptional changes that suppress ferroptosis, including the increased expression of SLC7A11, GPX4, and stearoyl-CoA desaturase 1 (SCD1), all of which drive resistance to ferroptosis, and loss of expression of the lipoxygenases ALOX12, ALOX12B, and ALOXE3; as noted above, these lipoxygenases promote ferroptosis in some contexts (Figure 4).…”

Section: Tumor Suppression and Immune Functionsmentioning

confidence: 99%

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Stockwell

2022

Cell

1,181

772

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“…In liver and pancreas cancer models, UTX can control the expression of negative regulators of mTOR such as DEPTOR , and its disruption prevents their transcription and facilitates tumorigenesis through increased mTORC1 activity (Revia et al, 2021). Additionally, while the mechanisms of MLL4 activity in liver cancer have not been examined, studies suggest that MLL4 suppresses skin carcinogenesis by promoting lineage stability and ferroptosis independently of MLL3 (Egolf et al, 2021). Our study demonstrates that MLL3 is both necessary and sufficient for efficient transcriptional activation of the CDKN2A locus that drives oncogene-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Soto‐Feliciano

Zhu

Huang

et al. 2022

Preprint

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Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3/KMT2C) histone methyltransferase occur in a range of solid tumors and heterozygous deletions encompassing MLL3 occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Mll3 cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded genes, Ink4a and Arf. Conversely, elevated MLL3 expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Mll3 restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in MLL3 and CDKN2A display mutual exclusivity in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

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MLL4 mediates differentiation and tumor suppression through ferroptosis

Abstract: This study reveals how epigenetic errors drive skin cancer initiation via altered cell fate and impaired ferroptosis.

Cited by 45 publications

References 58 publications

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

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