Downregulation of MLL3 in esophageal squamous cell carcinoma is required for the growth and metastasis of cancer cells

Xia, Manhui; Xu, Liang; Leng, Yunhua; Gao, Feng; Xia, Hong; Zhang, Diandian; Ding, Xuewu

doi:10.1007/s13277-014-2616-3

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…In the present study, MLL4 expression was identical to that of UTX, an observation that is concordant with a previous report by Lee et al 11 Although there have been no reports on the specific roles of these 2 histone-modifying enzymes in GBM biology, a few studies have reported on the oncogenic role of other enzymes, including SUV39H1, SUV39H2, KDM4A, UTX (KDM6A), and MLL4 in human breast cancer; 8,16 MLL4 and UTX in leukemia; 19,32 UTX in renal-cell carcinoma; 21 TERT and UTX (KDM6A) in bladder cancer; 13 MLL2 in medulloblastoma 5 and gastric cancer; 31 and MLL3 in esophageal cancer. 30 Recently, UTX and MLL4 were reported to coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells, 8 and downregulation of MLL3 was reported to be required for growth and metastasis in esophageal squamous cell carcinoma. 30 However, these studies did not investigate the clinical roles of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…30 Recently, UTX and MLL4 were reported to coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells, 8 and downregulation of MLL3 was reported to be required for growth and metastasis in esophageal squamous cell carcinoma. 30 However, these studies did not investigate the clinical roles of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…The pathological and clinical significance of several enzymes associated with methylation or demethylation of histone H3 lysine residues has been reported in other cancers. 8,13,16,19,30,32 Ubiquitously transcribed tetratricopeptide repeat gene on X chromosome (UTX) is an H3K27 demethylase that forms a complex with mixed lineage leukemia 4 (MLL4), an H3K4 methyltransferase, 11 and both are unique enzymes that are being fairly comprehensively studied in cancer. Therefore, we investigated the expression of these 2 enzymes and determined their clinical roles in patients with GBM.…”

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confidence: 99%

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Increased expression of the histone H3 lysine 4 methyltransferase MLL4 and the histone H3 lysine 27 demethylase UTX prolonging the overall survival of patients with glioblastoma and a methylated MGMT promoter

Kim¹,

Lee

Jang³

et al. 2017

Journal of Neurosurgery

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OBJECTIVE The purpose of the present study was to investigate the epigenetic and prognostic roles of an H3K4 methyltransferase (mixed lineage leukemia 4 [MLL4]) and H3K27 demethylase (ubiquitously transcribed tetratricopeptide repeat gene on X chromosome [UTX]) in progression-free survival (PFS) and overall survival (OS) of patients with glioblastoma (GBM) who were treated with radiotherapy, chemotherapy, or both after resection. In addition, the authors examined methylation at the promoter of the O-6-methylguanine-DNA methyltransferase ( MGMT) gene and other prognostic factors predicting length of PFS and OS in these patients. METHODS The medical records of 76 patients having a new diagnosis of histologically ascertained GBM in the period of January 2002 to December 2013 at the authors' institution were retrospectively reviewed. Immunohistochemical staining for MLL4 and UTX was performed on archived paraffin-embedded tissues obtained by biopsy or resection. The methylation status of the MGMT promoter in these tissues was determined by methylation-specific PCR analysis. RESULTS During the follow-up period (mean length 18.1 months, range 4.1-43.5 months), 68 (89.5%) of the patients died. The MGMT promoter was methylated in 49 patients (64.5%) and unmethylated in 27 (35.5%). The immunoreactivity pattern of UTX was identical to that of MLL4; increased expression of these 2 proteins was observed in samples from 34 patients (44.7%) and decreased expression in 42 patients (55.3%). The mean length of PFS was 9.2 months (95% CI 6.8-11.6 months). Extent of surgery, recursive partitioning analysis (RPA) class, and methylation status of the MGMT promoter were all associated with increased PFS in the multivariate analysis of factors predicting PFS. The mean length of OS was 18.6 months (95% CI 14.3-22.9 months). Patient age (p = 0.004), WHO performance status score (p = 0.019), extent of surgery (p = 0.007), RPA class (p = 0.036), methylation status of the MGMT promoter (p = 0.010), and increased expression of UTX-MLL4 (p = 0.001) were significantly associated with increased OS in multivariate analysis. Interestingly, in patients with an unmethylated MGMT promoter, immunoreactivity of UTX-MLL4 was not associated with changes in OS (p = 0.350). However, in the patients with a methylated MGMT promoter, increased UTX-MLL4 expression was strongly associated with increased OS (p < 0.001). CONCLUSIONS The results of this study suggest that increased expression of UTX-MLL4 positively influences the outcome of patients with GBM having a methylated MGMT promoter. Therefore, UTX-MLL4 immunoreactivity could be a useful predictor of the response to conventional treatment with radiotherapy or chemotherapy among GBM patients whose tumors have a methylated MGMT promoter.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased expression of the histone H3 lysine 4 methyltransferase MLL4 and the histone H3 lysine 27 demethylase UTX prolonging the overall survival of patients with glioblastoma and a methylated MGMT promoter

Kim¹,

Lee

Jang³

et al. 2017

Journal of Neurosurgery

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“…Another member of MLL family, MLL3 is reportedly mutated in multiple cancers. MLL3 regulates many migration-related genes and downregulation of MLL3 has a profound impact on the progression of ESCC [49]. Furthermore, Kim et al [50] showed that KMT2D/MLL4 expression is associated with poor survival in breast cancer and regulates tumor proliferation and invasiveness.…”

Section: Transcriptional Activation and Lysine Methylationmentioning

confidence: 99%

The Landscape of Histone Modification in Cancer Metastasis

Qiu¹,

Wang²,

Wu³

2018

Cancer Metastasis

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Metastasis represents one of the most devastating aspects of cancer. Epithelial to mesenchymal transition (EMT) has been shown to play a critical role in tumorigenic metastasis. During metastatic progression, both genetic and epigenetic modifications endow cancer cells with properties that modulate the capacity for metastatic success. Histone modification is profoundly altered in cancer cells and contributes to cancer metastasis by controlling different metastatic phenotypes. Here, we first review histone modifications and discuss their roles in EMT and metastasis, with a particular focus on histone methylation and acetylation. Second, we review the major histone modification enzymes that control chromatin in cancer metastasis. Third, we discuss the transcriptional regulation concerted by these enzymes with EMT transcription factors at different molecular layers. Finally, we discuss pharmacologic manipulation of histone modification enzymes for metastasis treatment. A comprehensive understanding of histone modification in metastasis will not only provide new insights into our knowledge of cancer progression and metastasis, but also offer a novel approach for the development of innovative therapeutic strategies.

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“…In fact, there are several reports about the oncogenic role of these histone modifying enzymes; UTX in renal cell carcinoma [41] and myeloid malignancies [42], MLL2 in medulloblastoma [43] and gastric cancer [44], JMJD5 in clear cell renal cell carcinoma [41], KDM5c in breast cancer [45]. Recently, UTX and MLL4 was suggested that they should regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells coordinately [46], and downregulation of MLL3 was suggested that this should be required for the growth and metastasis in esophageal squamous cell carcinoma [47]. However, they did not investigate clinical role of these enzymes, neither any role in apoptosis of tumor progression.…”

Section: Journal Of Clinical Epigeneticsmentioning

confidence: 99%

Dysregulation of Apoptosis Caused by Aberrant Histone Modification Influences on the Recurrence of Meningiomas

Kim¹

2017

J Clin Epigenet

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Background: Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study was aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. Materials and method:The medical records of 67 patients with AMs, as diagnosed during recent 13 years, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5).Results: Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than underexpression, and overexpression of Survivin, MDM2, and BCL2 had a shorter TTR than underexpression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than underexpression, and overexpression of KDM5c had a longer TTR than underexpression. However, in the multi-variate analysis of predicting factors for recurrence, underexpression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusion:This study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes.Keywords: Atypical meningioma; Apoptosis; Histone modification; Recurrence; Epigenetics a low recurrence rate after gross total resection (GTR) [5,6]. series have included only a few patients [9,10]. Even after GTR, tumor recurrence is observed after several years in some 20 to 30% of cases [11,12]. Thus, a reasonable organized therapeutic strategy could be instituted if recurrence could be predicted from surgical specimens, and for this reason many authors have investigated the histological indices of proliferative and apoptotic potential in resected AMs, such as, BCL2 [13,14], proliferating cell nuclear antigen [13], and Ki-67 cell cycle-specific nuclear antigen [15,16]. From these indices, researchers have attempted to establish the nature of the relationship between histological aggressiveness and the recurrence of AMs.

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Downregulation of MLL3 in esophageal squamous cell carcinoma is required for the growth and metastasis of cancer cells

Cited by 16 publications

References 25 publications

Increased expression of the histone H3 lysine 4 methyltransferase MLL4 and the histone H3 lysine 27 demethylase UTX prolonging the overall survival of patients with glioblastoma and a methylated MGMT promoter

Increased expression of the histone H3 lysine 4 methyltransferase MLL4 and the histone H3 lysine 27 demethylase UTX prolonging the overall survival of patients with glioblastoma and a methylated MGMT promoter

The Landscape of Histone Modification in Cancer Metastasis

Dysregulation of Apoptosis Caused by Aberrant Histone Modification Influences on the Recurrence of Meningiomas

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