Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

Wei, Lihui; Dong, Xiaoyu; Ren, Yong; Luo, Juanjuan; Liu, Pei; Su, Dongsheng; Yang, Xiaojun

doi:10.1038/s41419-017-0120-6

Cited by 59 publications

(46 citation statements)

References 33 publications

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“…Our results demonstrate that G9a not only sustains oncogenic signaling in the tumors, but also blocks their ability to undergo myogenic differentiation. Our data are consistent with a recent study that showed G9a-mediated repression of PTEN expression in non-small cell lung cancer (43). Previous studies have shown that the PI3K/AKT signaling is elevated in ARMS.…”

Section: G9a Knockdown Inhibits Tumorigenicity In Vivosupporting

confidence: 94%

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

et al. 2019

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Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. As transient and stable modifications to chromatin have emerged as critical mechanisms in oncogenic signaling, efforts to target epigenetic modifiers as a therapeutic strategy have accelerated in recent years. To identify chromatin modifiers that sustain tumor growth, we performed an epigenetic screen and found that inhibition of lysine methyltransferase G9a significantly affected the viability of ARMS cell lines. Targeting expression or activity of G9a reduced cellular proliferation and motility in vitro and tumor growth in vivo. Transcriptome and chromatin immunoprecipitation-sequencing analysis provided mechanistic evidence that the tumor-suppressor PTEN was a direct target gene of G9a. G9a repressed PTEN expression in a methyltransferase activitydependent manner, resulting in increased AKT and RAC1 activity. Re-expression of constitutively active RAC1 in G9adeficient tumor cells restored oncogenic phenotypes, demonstrating its critical functions downstream of G9a. Collectively, our study provides evidence for a G9a-dependent epigenetic program that regulates tumor growth and suggests targeting G9a as a therapeutic strategy in ARMS. Significance: These findings demonstrate that RAC1 is an effector of G9a oncogenic functions and highlight the potential of G9a inhibitors in the treatment of ARMS.

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Section: G9a Knockdown Inhibits Tumorigenicity In Vivosupporting

confidence: 94%

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

et al. 2019

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“…112 In addition, it has been shown that CpG hypermethylation mediates the epigenetic silencing of PTEN in lung cancer cells, causing acquired resistance to first-generation EGFR-TKIs. 113 Wang et al 114…”

Section: Fibroblast Growth Factor Receptor Signalingmentioning

confidence: 99%

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

Tripathi

Pandey

Rengasamy

et al. 2020

Medicinal Research Reviews

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to a substantial improvement in the prognosis of lung cancer patients by explicitly targeting the activating mutations within the EGFR. Initially, patients harboring tumors with EGFR mutations show progressionfree survival and improvement in the response rates toward all-generation EGFR-TKIs; however, these agents fail to deliver the intended results in the long-term due to drug resistance. Therefore, it is necessary to recognize specific cardinal mechanisms that regulate the resistance phenomenon. Understanding the intricate mechanisms underlying EGFR-TKIs resistance in lung cancer could provide cognizance for more advanced targeted therapeutics. The present review features insights into current updates on the discrete mechanisms, including secondary or tertiary mutations, parallel and downstream signaling pathways, acquiring an epithelial-to-mesenchymal transition (EMT) signature, microRNAs (miRNAs), and epigenetic alterations, which lead to intrinsic and acquired resistance against EGFR-TKIs in lung cancer. In addition, this paper also reviews current possible strategies to overcome this issue using combination treatment of recently developed MET inhibitors, allosteric inhibitors or immunotherapies, transformation of EMT, targeting miRNAs, and epigenetic alterations in intrinsic and acquired EGFR-TKIs resistant lung cancer. In conclusion, multiple factors are responsible for intrinsic and acquired resistance to EGFR-TKIs and understanding of the detailed molecular mechanisms, and recent advancements in pharmacological studies are needed to develop new strategies to overcome intrinsic and acquired EGFR-TKIs resistance in lung cancer.

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“…With the continuous exploration of the pathogenesis of NSCLC, more and more molecules have been found to be enrolled in the occurrence and progression of this disease. 18,19 Previous studies have found that FSTL family members have abnormal expression in tumors and are involved in the tumorigenesis and cancer progression. For example, FSTL1 expression is down-regulated in NSCLC, and its overexpression can significantly inhibit cell proliferation, migration and invasion, and induce apoptosis, 20 while FSTL1 expression is up-regulated in hepatocellular carcinoma, and knocking down its expression can promote apoptosis and inhibit cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

<p>Up-Regulation of FSTL3, Regulated by lncRNA DSCAM-AS1/miR-122-5p Axis, Promotes Proliferation and Migration of Non-Small Cell Lung Cancer Cells</p>

Gao¹,

Chen²,

Wang³

et al. 2020

OTT

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Background: Follistatin-like 3 (FSTL3) binds and inactivates activin, a growth factor with cell growth and differentiation. Previous studies reported that it is overexpressed in invasive breast cancers, and its expression and function in non-small cell lung cancer (NSCLC) remain unclear. Materials and Methods: Immunohistochemistry was employed to probe the expression of FSTL3 in NSCLC tissues. Real-time PCR (RT-PCR) was applied to detect the expression of lncRNA DSCAM-AS1 and miR-122-5p. A549 cells and H1299 cells were used as cell models. The biological influence of FSTL3 on cells was studied using CCK-8 assay, wound healing assay and transwell assay in vitro, respectively. In vivo subcutaneous xenotransplanted tumor model and tail vein injection model in mice were also constructed to validate the roles of FSTL3. Interactions between miR-122-5p and FSTL3, DSCAM-AS1 and miR-122-5p were determined by bioinformatics analysis, RT-PCR, and dual-luciferase reporter assay. Results: FSTL3 and DSCAM-AS1 were remarkably up-regulated in NSCLC samples, and miR-122-5p was down-regulated. FSTL3 was associated with worse prognosis of NSCLC patients. FSTL3 knockdown markedly inhibited the viability, migration and invasion of NSCLCs in vitro and in vivo. DSCAM-AS1 could down-regulate miR-122-5p via sponging it, and FSTL3 was a target gene of miR-122-5p. Conclusion: Taken together, our study identified that FSTL3 was a new oncogene of NSCLC, which was regulated by DSCAM-AS1 and miR-122-5p. These findings suggested that FSTL3, DSCAM-AS1 and miR-122-5p might serve as a new valuable therapeutic target for NSCLC.

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Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

Cited by 59 publications

References 33 publications

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

<p>Up-Regulation of FSTL3, Regulated by lncRNA DSCAM-AS1/miR-122-5p Axis, Promotes Proliferation and Migration of Non-Small Cell Lung Cancer Cells</p>

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