KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth

Riverso, Maria; Montagnani, Valentina; Stecca, Barbara

doi:10.1038/onc.2016.481

Cited by 84 publications

(68 citation statements)

References 58 publications

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“…EGFR has been reported to promote c‐Myc expression, another Yamanaka factor, by activating its downstream signaling pathway PI3K/AKT . RAF/MEK/ERK is also one of downstream signaling pathways of EGFR and is reported to positively regulate KLF4 expression . We believe that EGFR might promote KLF4 expression by activating RAF/MEK/ERK signaling pathway.…”

Section: Discussionmentioning

confidence: 82%

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

Pang

Yuan

et al. 2019

Molecular Carcinogenesis

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Sorafenib is the standard first‐line systemic chemotherapeutic drugs for advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is frequently observed in clinical practice. In this study, we first produced three sorafenib resistance (SR) HCC cell lines by using two human HCC cell lines (Hep3B and Huh7) and a human primary HCC cell line. We identified that epidermal growth factor receptor (EGFR) and Kruppel‐like factor 4 (KLF4) are dramatically increased in the three SR HCC cell lines. Either inhibition of tyrosine kinase activity of EGFR with Erlotinib/Icotinib or inhibition of KLF4 expression with short hairpin RNA recovered the response of three SR HCC cell lines to sorafenib, suggesting the critical roles of EGFR tyrosine kinase and KLF4 on inducing SR. Luciferase activity and chromatin immunoprecipitation assays further determined that KLF4 promoted EGFR expression through inducing its transcription by directly binding to its promoter. EGFR, conversely, could also promote KLF4 expression through inducing its transcription by binding to its promoter in a tyrosine kinase‐dependent manner, suggesting that a positive feedback loop formed by EGFR and KLF4 further amplifies their effects on inducing SR. Up to now, our findings that KLF4 induces the development of SR and it cooperates with EGFR to form a positive feedback loop to amplify their SR‐inducing abilities have rarely been reported. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC.

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Section: Discussionmentioning

confidence: 82%

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

Pang

Yuan

et al. 2019

Molecular Carcinogenesis

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“…These studies led us to define a novel regulatory role for SUV39H1 in modulating E2F1 activity through loss of RB function. SUV39H1-mediated E2F1 regulation is relevant in light of previous work, showing that E2F1 expression in melanoma tissues was significantly higher than in normal skin samples (44), and higher E2F1 levels are associated with aberrant RAS-RAF1-MEK-ERK signaling pathway activation, which is critical for melanoma growth and maintenance (45).…”

Section: Discussionmentioning

confidence: 86%

SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development

et al. 2018

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Melanoma is among the most aggressive and treatment-resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing, but the significance of suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9-specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1-mediated H3K9 trimethylation facilitates retinoblastoma ( RB) 1 promoter CpG island methylation by interacting with DNA methyltransferase 3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)-MEK-ERK signaling pathway activation. In a synergistic model with B16-F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1-overexpressing B16-F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.-Kim, G., Kim, J.-Y., Lim, S.-C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.

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“…105 In addition, depletion of KLF4 inhibits melanoma xenograft growth in vivo. 106 High expression of KLF4, an oncogene in human breast CSCs, is correlated with an aggressive phenotype in canine mammary tumors. 107 These studies suggest that KLF4 has different functions in different CSCs.…”

Section: Major Transcription Factors In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth

Cited by 84 publications

References 58 publications

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

SUV39H1/DNMT3A‐dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development

Targeting cancer stem cell pathways for cancer therapy

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