Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Jiao, Jing; Meng, Xianguang; An, Yunhe; Han, Chen; Huang, Shuhong

doi:10.18632/aging.102750

Cited by 29 publications

(32 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, CM-272 is a potent dual inhibitor of G9a (a type of histone methyltransferase) and DNMTs for the treatment of hematological malignancies [ 119 ]. G9a is responsible for methylating lysine 9 of histone 3 (H3K9), and overexpression of G9a leads to increased tumor progression in some tumors [ 120 , 121 ]. It is involved in the transcriptional repression of the tumor suppressor gene PTEN , and upregulation of the G9a gene and downregulation of the PTEN gene can predict poor overall survival [ 122 ].…”

Section: Targeting Dnmtsmentioning

confidence: 99%

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

Zhang

Yang

et al. 2020

Cancers

160

View full text Add to dashboard Cite

DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy.

show abstract

Section: Targeting Dnmtsmentioning

confidence: 99%

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

Zhang

Yang

et al. 2020

Cancers

160

View full text Add to dashboard Cite

show abstract

“…It has been observed that the expression of G9a is upregulated in a number of cancers, including aggressive lung cancer, multiple myeloma, aggressive ovarian carcinoma, brain cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and malignant melanoma (Wozniak et al, 2007;Gao et al, 2013;Hua et al, 2014;Lehnertz et al, 2014;Hu et al, 2019;Dang et al, 2020). Higher G9a expression levels have often been associated with poor prognosis (Chen et al, 2010;Ke et al, 2014;Zhang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

Zhang

Zhong

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Glioblastoma is an aggressive and difficult to treat cancer. Recent data have emerged implicating that histone modification level may play a crucial role in glioma genesis. The histone lysine methyltransferase G9a is mainly responsible for the mono- and di-methylation of histone H3 lysine 9 (H3K9), whose overexpression is associated with a more aggressive phenotype in cancer. However, the detailed correlations between G9a and glioblastoma genesis remain to be further elucidated. Here, we show that G9a is essential for glioblastoma carcinogenesis and reveal a probable mechanism of it in cell proliferation control. We found that G9a was highly expressed in glioblastoma cells, and knockdown or inhibition of G9a significantly repressed cell proliferation and tumorigenesis ability both in vitro and in vivo. Besides, knockdown or inhibition of G9a led to a cell cycle arrest in G2 phase, as well as decreased the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1, while it induced the activation of autophagy. Further investigation showed that G9a deficiency induced cell proliferation suppression, and activation of autophagy was rescued by overexpression of the full-length c-Myc. Chromatin immunoprecipitation (ChIP) assay showed that G9a was enriched on the −2267 to −1949 region of the c-Myc promoter in LN-229 cells and the −1949 to −1630 region of the c-Myc promoter in U-87 MG cells. Dual-luciferase reporter assay showed that c-Myc promoter activity was significantly reduced after knockdown or inhibition of G9a. Our study shows that G9a controls glioblastoma cell proliferation by transcriptionally modulating oncogene c-Myc and provides insight into the capabilities of G9a working as a potential therapeutic target in glioblastoma.

show abstract

“…Conversely, G9a inhibition downregulated HES1 in both protein level and TF activity in GSC, which has been reported to promote EMT and cell migration [90]. The underlying regulation can be explained by the function of G9a as a coactivator, since it has been reported that G9a activates the Notch signaling pathway by regulating Notch1 and Hes1 in cancer progression of melanoma[91]. Another possibility is that G9a might promote AKT activity which in turn upregulates HES1[61, 92].…”

Section: Discussionmentioning

confidence: 99%

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

Liao

Suen

Luk

et al. 2020

Preprint

View full text Add to dashboard Cite

Epithelial-mesenchymal transition (EMT) is a phenomenon in which epithelial cells acquire mesenchymal traits. It contributes to organogenesis and tissue homeostasis, as well as stem cell differentiation. Emerging evidence indicates that heterogeneous expression of EMT gene markers presents in sub-populations of germline stem cells (GSCs). However, the functional implications of such heterogeneity are largely elusive. Here, we unravelled an EMT-like process in GSCs by in vitro extracellular matrix (ECM) model and single-cell genomics approaches. Through modulating ECM, we demonstrated that GSCs exist in interconvertible epithelial-like and mesenchymal-like cell states. GSCs gained higher migratory ability after transition to a mesenchymal-like cell state, which was largely mediated by the TGF-β signaling pathway. Dynamics of epigenetic regulation at the single-cell level was also found to align with the EMT-like process. Chromatin accessibility profiles generated by single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) clustered GSCs into epithelial-like and mesenchymal-like states, which were associated with differentiation status. The high-resolution data revealed novel regulators in the EMT-like process, including transcription factors Zeb1 and Hes1. We further identified putative enhancer-promoter interactions and cis-co-accessibility networks at loci such as Tgfb1, Notch1 and Lin28a. Importantly, we demonstrated that histone methyltransferase G9a promoted the GSC EMT-like process in vitro and contributed to neonatal germ cell migration in vivo. Our work thus provides the foundation for understanding the EMT-like process and a comprehensive resource for future investigation of epigenetic regulatory networks in GSCs.

show abstract

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Cited by 29 publications

References 60 publications

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

Contact Info

Product

Resources

About