UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

Ezponda, Teresa; Dupéré-Richér, Daphne; Will, Christine M.; Small, Eliza C.; Varghese, Nobish; Patel, Tej; Nabet, Behnam; Popovic, Relja; Oyer, Jon A.; Bulic, Marinka; Zheng, Yupeng; Huang, Xiaoxiao; Shah, Mrinal Y.; Maji, Sayantan; Riva, Alberto; Occhionorelli, Manuela; Tonon, Giovanni; Kelleher, Neil L.; Keats, Jonathan J.; Licht, Jonathan D.

doi:10.1016/j.celrep.2017.09.078

Cited by 110 publications

(112 citation statements)

References 41 publications

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“…Direct and indirect evidence suggests that KDM6A is sensitive to changes in oxygen levels within the cells . Inactivation of KDM6A is enriched in aggressive tumours, including PDAC . Interrogating the International Cancer Genome Consortium (ICGC) cohort, we found that a hypoxia transcriptional signature is enriched in PDAC characterised by KDM6A inactivation (see supplementary material, Figure S6A).…”

Section: Resultsmentioning

confidence: 78%

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

Amato¹,

Mafficini²,

Hirabayashi

et al. 2018

The Journal of Pathology

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Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1 . No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐ activating mutations, we found inactivating mutations of epigenetic regulators ( KDM6A , TET1 , BAP1 ) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 78%

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

Amato¹,

Mafficini²,

Hirabayashi

et al. 2018

The Journal of Pathology

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“…In addition to the H3K37me2/3 demethylating function, KDM6A has been proposed to have demethylase‐independent functions in the regulation of gene expression through interacting with other transcriptional regulators (Van der Meulen et al , ; Ezponda et al , ). KDM6A can be a component of MLL2 complex, a histone H3K4 methyltransferase complex (Van der Meulen et al , ).…”

Section: Discussionmentioning

confidence: 99%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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Diabetic nephropathy is the leading cause of end‐stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM 6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up‐regulation of its downstream target KLF 10. Overexpression of KLF 10 in podocytes not only represses multiple podocyte‐specific markers including nephrin, but also conversely increases KDM 6A expression. We further show that KLF 10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM 6A or KLF 10 in mice significantly suppresses diabetes‐induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM 6A and KLF 10 proteins or mRNA s are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM 6A– KLF 10 feedback loop may be beneficial to attenuate diabetes‐induced kidney injury.

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“…6 Examples include UC, 49 lung cancer, 58 pancreatic squamous carcinoma, 32 multiple myeloma, 59 and some breast cancer cell lines. In several cancer types, inhibitors of the EZH2 methyltransferase like GSK126 are more efficacious in cell lines and mouse models with UTX loss of function.…”

Section: Clinical Applicationsmentioning

confidence: 99%

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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The lysine‐specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T‐cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X‐chromosome, but both copies are expressed, may account for gender‐specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor‐suppressive function.

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UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

Cited by 110 publications

References 41 publications

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

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