Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges

Chen, Yu‐Chen; Liu, Xinran; Li, Yangkai; Quan, Chuntao; Zheng, Ling; Huang, Kun

doi:10.1016/j.csbj.2018.06.001

Cited by 50 publications

(37 citation statements)

References 191 publications

(237 reference statements)

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“…SETDB1 is an H3K9-specific histone methyltransferase that has been described as a repressive transcription factor involved in methylation and silencing of various genes (Fei et al, 2015;Riviere et al, 2016;Karanth et al, 2017). SETDB1 levels are greatly increased in numerous cancers, including lung cancer (Lafuente-Sanchis et al, 2016;Chen B. et al, 2018), and is an important epigenetic regulator involved in control of histone methylation in tumorigenesis, dysregulation of histone methylation, and aberrant miRNA profiling, contributing to tumorigenesis and progression (Chen Y. et al, 2018;Michalak et al, 2019). Moreover, DNA methylation can directly influence miRNA biogenesis (Glaich et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Liu

et al. 2020

Front. Cell Dev. Biol.

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Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Liu

et al. 2020

Front. Cell Dev. Biol.

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“…The most abundant histone modifications are acetylation, phosphorylation, ubiquitination and methylation by specific chromatin-modifying enzymes. Writing of methyl marks on lysine residues of histone proteins is performed by histone lysine methyl transferases, of which nine were described to be associated with lung cancer [6]. Until recently, all known histone lysine methyl transferases belonged to the su(var)3-9, enhancer-of-zeste and trithorax (SET) domain family with the only exception being DOT1L that belongs to the seven-β-strand family [7,8].…”

Section: Introductionmentioning

confidence: 99%

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

et al. 2020

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Background: Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 that acts as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study, we aimed to identify the function of KMT9 in lung cancer. Methods:We unraveled the KMT9 transcriptome and proteome in A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry and linked them with functional cell culture, real-time proliferation and flow cytometry assays. Results:We show that KMT9α and -β subunits of KMT9 are expressed in lung cancer tissue and cell lines. Importantly, high levels of KMT9α correlate with poor patient survival. We identified 460 genes that are deregulated at the RNA and protein level upon knock-down of KMT9α in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9α inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells. Conclusions:The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy. Additional file 5. Certificate NCI-H2087. Results and certificate of STRprofiling and cell authentication. Additional file 6. Certificate CRL-7000. Results and certificate of STRprofiling and cell authentication. "HS 1.Lu" is a synonym of CRL-7000. Additional file 7. Certificate IMR-90. Results and certificate of STR-profiling and cell authentication. Additional file 8. KMT9α expression is significantly increased in stage 1 and 3 lung adenocarcinoma from the TCGA cohort. a TCGA lung adenocarcinoma samples were divided according to stage and the KMT9α expression analyzed. Data represent interquartile range including minimum, 25th percentile, median, 75th percentile and maximum values. Significance was accessed by t test. b TCGA lung adenocarcinoma samples were divided according to histopathologic subtypes and the KMT9α expression analyzed. Data represent interquartile range including minimum, 25th percentile, median, 75th percentile and maximum values. Significance was accessed by t test. Subgroups with p-value < 0.05 when compared to normal are marked by "*". Abbreviations NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; SSC: Side scatter; FSC: Forward scatter; RNA-Seq: RNA sequencing; qRT-PCR: Quantitative real-time polymerase chain reaction. of Cologne,

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“…In recent years, new compounds with different mechanisms of action have been developed. Unlike the first class of DOT1L inhibitors, mimetic peptide molecules such as compound (8), shown in Figure 3, do not determine total inhibition of DOT1L activity, but bind AF9/ENL, thus blocking recruitment of DOT1L to MLL target genes and reducing levels of HOAX9 [110].…”

Section: Dot1l Inhibitorsmentioning

confidence: 99%

“…As well as modulating gene expression, this modification is involved in X-chromosome inactivation [3,4], DNA damage repair [5], and in the determination and differentiation of embryonic stem cells [6,7]. However, it is widely reported that dysregulation of HMT expression and activity is frequently observed in cancer [8][9][10][11]. Two main histone residues, arginine and lysine groups, are methylated by HMTs.…”

Section: Introductionmentioning

confidence: 99%

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

2019

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Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di-and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results. ARTICLE HISTORY

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Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges

Cited by 50 publications

References 191 publications

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

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