Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumors

Dhar, S.; Lee, Min Gyu

doi:10.18632/oncotarget.27988

Cited by 29 publications

(33 citation statements)

References 89 publications

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“…Antisense lncRNAs located in the nucleus can recruit DNA, histone-modifying enzymes, or transcription factors to specific sites to cis-regulate the expression of sense mRNAs ( 53 ). Our study demonstrated that MLL2, a member of the MLL family and a component of the ASC-2/NCOA6 complex (ASCOM), has histone methylation activity and thus participates in transcriptional activation ( 54 ). The FOXP4-AS1 located in the nucleus could increase the expression of FOXP4 by interacting with MLL2.…”

Section: Discussionmentioning

confidence: 96%

LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4

Niu

Wang

et al. 2021

Front. Oncol.

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Malignant tumors are a grave threat to human health. Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignant tumor. China has a high incidence of ESCC, and its morbidity and mortality are higher than the global average. Increasingly, studies have shown that long noncoding RNAs (lncRNAs) play a vital function in the occurrence and development of tumors. Although the biological function of FOXP4-AS1 has been demonstrated in various tumors, the potential molecular mechanism of FOXP4-AS1 in ESCC is still poorly understood. The expression of FOXP4 and FOXP4-AS1 was detected in ESCC by quantitative real-time PCR (qRT–PCR) or SP immunohistochemistry (IHC). shRNA was used to silence gene expression. Apoptosis, cell cycle, MTS, colony formation, invasion and migration assays were employed to explore the biological functions of FOXP4 and FOXP4-AS1. The potential molecular mechanism of FOXP4-AS1 in ESCC was determined by dual-luciferase reporter, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP). Here, we demonstrated that FOXP4-AS1 was significantly increased in ESCC tissues and cell lines, associated with lymph node metastasis and TNM staging. Cell function experiments showed that FOXP4-AS1 promoted the proliferation, invasion and migration ability of ESCC cells. The expression of FOXP4-AS1 and FOXP4 in ESCC tissues was positively correlated. Further research found that FOXP4-AS1, upregulated in ESCC, promotes FOXP4 expression by enriching MLL2 and H3K4me3 in the FOXP4 promoter through a “molecular scaffold”. Moreover, FOXP4, a transcription factor of β-catenin, promotes the transcription of β-catenin and ultimately leads to the malignant progression of ESCC. Finally, FOXP4-AS1 may be a new therapeutic target for ESCC.

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Section: Discussionmentioning

confidence: 96%

LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4

Niu

Wang

et al. 2021

Front. Oncol.

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“…As the largest H3K4 methyltransferase among them, KMT2D also represents the most frequently mutated gene in multiple human cancers, including OSCC [ 1 , 2 , 8 ]. Nonetheless, the role of KMT2D in tumor development remains largely controversial [ 8 , 9 ]. Using a gene-editing mouse model, Dhar and Alam showed that tissue-specific ablation of Kmt2d in the brain and lung promoted tumorigenesis [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Of chromatin modifiers, histone-lysine N -methyltransferase 2D (KMT2D) is among the most frequently mutated genes in multiple human cancers, including OSCC [ 8 , 9 ]. The Cancer Genome Atlas Network (TCGA) revealed that the mutation frequency of KMT2D in head and neck squamous cell carcinoma (HNSCC) was 18% among 279 HNSCC patients [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, through whole-exon sequencing of 86 OSCC tissue samples, we revealed that the mutation type of KMT2D in OSCC was mainly missense mutation [ 11 ]. Although loss-of-function mutations, such as truncation and missense mutations, account for certain types of mutated KMT2D, KMT2D also appears to play an oncogenic role in a context- or tissue-specific manner [ 8 , 9 ]. In in vitro cell line experiments, knockdown of KMT2D reduced the proliferation and invasion of pancreatic and breast cancer cells [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Histone methyltransferase KMT2D cooperates with MEF2A to promote the stem-like properties of oral squamous cell carcinoma

Wang

et al. 2022

Cell Biosci

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Background Epigenetic reprogramming is involved in multiple steps of human cancer evolution and is mediated by a variety of chromatin-modifying enzymes. Specifically, the histone lysine methyltransferase KMT2D is among the most frequently mutated genes in oral squamous cell carcinoma (OSCC). However, the mechanisms by which KMT2D affects the development of OSCC remain unclear. Results In the present study, we found that the expression of KMT2D was elevated in OSCC compared to paracancerous specimens and was correlated with a more advanced tumor grade. More importantly, knockdown of KMT2D impaired their reconstitution in patient-derived organoids and decreased the expression of CD133 and β-catenin in OSCC cells. In in vitro and in vivo models, knockdown of KMT2D reduced the colony formation, migration and invasion abilities of OSCC cells and delayed tumor growth. Mechanistically, the dual-luciferase reporter and co-immunoprecipitation assays in two individual OSCC cell lines indicated that KMT2D may cooperate with MEF2A to promote the transcription activity of CTNNB1, thereby enhancing WNT signaling. Conclusion The upregulation of KMT2D contributes to stem-like properties in OSCC cells by sustaining the MEF2A-mediated transcriptional activity of CTNNB1.

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“…The prevailing hypothesis is that alterations in KMT2 function contribute to carcinogenesis through the modification of histone methylation patterns; thus, novel therapeutic agents targeting other histone demethylases may be an option to inhibit disease recurrence and/or progression in tumors with KMT2D alterations [35,36]. Given that the data from UTUC patients from the TCGA show that KMT2D alterations are co-expressed with fibroblast growth factor receptor (FGFR3) alterations in more than half of the cases, a plausible treatment strategy may also be a combination of FGFR3 inhibitors with histone demethylase inhibitors [37].…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis and Mutational Status of Histone Methyltransferase KMT2D at Different Upper Tract Urothelial Carcinoma Locations

Laukhtina

Lemberger

Bruchbacher

et al. 2021

JPM

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The gene coding for histone methyltransferase KMT2D is found among the top mutated genes in upper tract urothelial carcinoma (UTUC); however, there is a lack of data regarding its association with clinicopathologic features as well as survival outcomes. Therefore, we aimed to investigate KMT2D expression, mutation patterns, and their utility as prognostic biomarkers in patients with UTUC. A single-center study was conducted on tumor specimens from 51 patients treated with radical nephroureterectomy (RNU). Analysis of KMT2D protein expression was performed using immunohistochemistry (IHC). Customized next-generation sequencing (NGS) was used to assess alterations in KMT2D exons. Cox regression was used to assess the relationship of KMT2D protein expression and mutational status with survival outcomes. KMT2D expression was increased in patients with a previous history of bladder cancer (25% vs. 0%, p = 0.02). The NGS analysis of KMT2D exons in 27 UTUC tumors revealed a significant association between pathogenic KMT2D variants and tumor location (p = 0.02). Pathogenic KMT2D variants were predominantly found in patients with non-pelvic or multifocal tumors (60% vs. 14%), while the majority of patients with a pelvic tumor location (81% vs. 20%) did not harbor pathogenic KMT2D alterations. Both IHC and NGS analyses of KMT2D failed to detect a statistically significant association between KMT2D protein or KMT2D gene alteration status and clinical variables such as stage/grade of the disease or survival outcomes (all p > 0.05). KMT2D alterations and protein expression were associated with UTUC features such as multifocality, ureteral location, and previous bladder cancer. While KMT2D protein expression and KMT2D mutational status do not seem to have prognostic value in UTUC, they appear to add information to improve clinical decision-making regarding the type of therapy.

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Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumors

Cited by 29 publications

References 89 publications

LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4

LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4

Histone methyltransferase KMT2D cooperates with MEF2A to promote the stem-like properties of oral squamous cell carcinoma

Expression Analysis and Mutational Status of Histone Methyltransferase KMT2D at Different Upper Tract Urothelial Carcinoma Locations

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