Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate

Chakraborty, Abhishek A.; Laukka, Tuomas; Myllykoski, Matti; Ringel, Alison E.; Booker, Matthew A.; Tolstorukov, Michael Y.; Meng, Yuzhong Jeff; Meier, Samuel R.; Jennings, Rebecca B.; Creech, Amanda L.; Herbert, Zachary T.; McBrayer, Samuel K.; Olenchock, Benjamin A.; Jaffe, Jacob D.; Haigis, Marcia C.; Beroukhim, Rameen; Signoretti, Sabina; Koivunen, Peppi; Kaelin, William G.

doi:10.1126/science.aaw1026

Cited by 314 publications

(287 citation statements)

References 55 publications

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“…In our cancer type specific and pan-cancer analysis we observed the presence of several mutations that deserve further interrogation on a mechanistic level. For example the histone demethylase encoded by KDM6A, where gene deletion has long been associated with the Kabuki immunodeficiency syndrome (Ng et al 2010), is also known to be associated with immune relevant processes including the type I interferon (Li et al 2017) and hypoxia response (Chakraborty et al 2019). In metastatic melanoma we observed ITGAX (alias CD11c), a marker expressed on myeloid cells with well-known impact on classical and monocytic dendritic cell function (Wculek et al 2019), is more frequently mutated in non-T cell-inflamed tumors.…”

Section: Discussionmentioning

confidence: 75%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational profile may also dictate response with some oncogenes (i.e. WNT/β-catenin) known to mediate immuno-suppression. Building on these observations we performed a multi-omic analysis of human cancer correlating the T cell-inflamed gene expression signature with the somatic mutanome and transcriptome for different immune phenotypes, by tumor type and across cancers. Strong correlations were noted between mutations in oncogenes and non-T cellinflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c and genes with unknown functions. Conversely, we observe many genes associating with the T cell-inflamed phenotype including VHL and PBRM1, among others.Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion broadly active across cancer types including HIF1A and MYC. Novel examples from specific tumors include sonic hedgehog signaling in ovarian cancer or hormone signaling and novel transcription factors across multiple tumors. Using network analysis, somatic and transcriptomic events were integrated, demonstrating that most non-T cell-inflamed tumors are influenced by multiple pathways. Validating these analyses, we observe significant inverse relationships between protein levels and the T cell-inflamed gene signature with examples including NRF2 in lung, ERBB2 in urothelial and choriogonadotropin in cervical cancer. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms.These results nominate molecular targets and drugs potentially available for immediate translation into clinical trials for patients with cancer.

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Section: Discussionmentioning

confidence: 75%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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“…Additionally, L2HG has been shown to promote the development of epigenetic cell-to-cell variability 17 . Intriguingly, more recent studies indicate that JHDM histone demethylases can directly sense cellular oxygen levels to regulate cell fate decisions 59,60 . In analogy, it might be plausible that αKG-dependent dioxygenases including TET DNA hydroxylases and JHDM histone demethylases could serve as metabolic sensors by detecting intratumor 2HG levels, which may reflect profound metabolic disturbances accompanied by underlying acidosis and hypoxia implicated in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

Kusi

Zand

Lin

et al. 2020

Preprint

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17Metabolic reprogramming in cancer cells not only sustains bioenergetic and biosynthetic needs 18 but also influences transcriptional programs, yet how chromatin regulatory networks are rewired 19 by altered metabolism remains elusive. Here we investigate genome-scale chromatin remodeling 20 in response to 2-hydroxyglutarate (2HG) oncometabolite using single-cell assay for transposase 21 accessible chromatin with sequencing (scATAC-seq). We find that 2HG enantiomers differentially 22 disrupt exquisite control of epigenome integrity by limiting α-ketoglutarate (αKG)-dependent DNA 23 and histone demethylation, while enhanced cell-to-cell variability in the chromatin regulatory 24 landscape is most evident upon exposure to L2HG enantiomer. Despite the highly heterogeneous 25 responses, 2HG largely recapitulates two prominent hallmarks of the breast cancer epigenome, 26 i.e., global loss of 5-hydroxymethylcytosine (5hmC) and promoter hypermethylation, particularly 27 at tumor suppressor genes involved in DNA damage repair and checkpoint control. Single-cell 28 mass cytometry further demonstrates downregulation of BRCA1, MSH2 and MLH1 in 2HG-29 responsive subpopulations, along with acute reversal of chromatin remodeling upon withdrawal. 30 Collectively, this study provides a molecular basis for metabolism-epigenome coupling and 31 identifies metabolic vulnerabilities imposed on the breast cancer epigenome. 33 As a dynamic system, cancer cells continuously adapt to the fluctuating microenvironment by 34 rerouting metabolic fluxes and evolve from early initiation through progression and 35 dissemination 1,2 . Metabolic reprogramming in cancer cells facilitates energy production and 36 macromolecular synthesis to fuel cell proliferation 3,4 . In addition to supporting bioenergetic and 37 biosynthetic needs, altered metabolism involves promiscuous production of non-canonical 38 metabolic intermediates, which have been described as metabolic waste products or metabolite 39 damage 5,6 . Recent studies suggest that these previously uncharacterized metabolites including 40 oncometabolites are linked to 'non-metabolic' signaling mechanisms in cell-type-specific fate 41 decisions 7 . 42 The oncometabolite 2-hydroxyglutarate (2HG) occurs as two enantiomers and 43 accumulates up to millimolar concentrations in a broad range of hematological and solid 44 malignancies 8,9 . Somatic mutations in isocitrate dehydrogenase genes, IDH1 and IDH2, found in 45 glioma and acute myeloid leukemia (AML) result in stereospecific production of the D-enantiomer 46 (D2HG) 10,11 , while breast tumors frequently exhibit elevated levels of 2HG despite the lack of IDH 47 mutations 12,13 . Recent studies indicate that the L-enantiomer (L2HG) can accumulate under 48 acidic 14,15 and hypoxic conditions 16,17 that often coexist in the tumor microenvironment, yet the 49 potential sources and functions of L2HG are less well established. Both enantiomers structurally 50 resemble α-ketoglutarate (αKG), a key intermediate ...

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“…Kaelin's data suggest that hypoxia directly downregulates KDM6A, which has a low affinity for O 2 . These results may have implications for understanding gene expression in hypoxic environments, including tumors …”

Section: From Metabolic Dysfunction To Therapeuticsmentioning

confidence: 95%

“…These results may have implications for understanding gene expression in hypoxic environments, including tumors. 38 The second half of Kaelin's talk focused on IDH1mutant glioma. Mutations in IDH1 or IDH2 can cause aberrant activity that results in the accumulation of 2-hydroxyglutarate, which can inhibit the activity of many enzymes that use α-ketoglutarate, including α-ketoglutarate-dependent dioxygenases described above.…”

Section: From Metabolic Dysfunction To Therapeuticsmentioning

confidence: 99%

Leveraging insights into cancer metabolism—a symposium report

Cable¹,

Finley

et al. 2019

Annals of the New York Academy of Sciences

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Tumor cells have devised unique metabolic strategies to garner enough nutrients to sustain continuous growth and cell division. Oncogenic mutations may alter metabolic pathways to unlock new sources of energy, and cells take the advantage of various scavenging pathways to ingest material from their environment. These changes in metabolism result in a metabolic profile that, in addition to providing the building blocks for macromolecules, can also influence cell signaling pathways to promote tumor initiation and progression. Understanding what pathways tumor cells use to synthesize the materials necessary to support metabolic growth can pave the way for new cancer therapeutics. Potential strategies include depriving tumors of the materials needed to grow or targeting pathways involved in dependencies that arise by virtue of their altered metabolis.

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Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate

Cited by 314 publications

References 55 publications

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

Leveraging insights into cancer metabolism—a symposium report

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