c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma

Wang, Lei; Zhang, Xiang; Jia, Lintao; Hu, Songhua; Zhao, Jing; Yang, Jiandong; Wen, Weihong; Wang, Zhe; Wang, Tao; Zhao, Jun; Wang, Rui‐An; Meng, Yanyan; Nie, Yongzhan; Dou, Kefeng; Chen, Si-Yi; Yao, Libo; Fan, Daiming; Zhang, Rui; Yang, An‐Gang

doi:10.1002/hep.26720

Cited by 142 publications

(122 citation statements)

References 43 publications

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“…[6][7][8] We found all the cases of Burkitt lymphoma and double hit lymphoma show high MYC expression (80-100 and 50-90% tumor cells are positive, respectively), which correlates with high EZH2 expression in these neoplasms; however, only 20% of tumor cells in the diffuse large B-cell lymphoma cases show positive MYC staining. These results suggest that MYC may preferentially upregulate EZH2 expression in Burkitt lymphoma and double hit lymphoma, compared with diffuse large B-cell lymphoma.…”

Section: Discussionmentioning

confidence: 78%

“…In addition, MYC can directly bind to and activate the EZH2 promoter. [6][7][8] In epithelial ovarian cancer, NF-YA, the regulatory subunit of CCAAT-binding transcription factor, is highly expressed and upregulates EZH2 at the transcriptional level. 9 In colorectal carcinoma, STAT3 is constitutively activated, directly binds to the EZH2 promoter, and regulates its expression, which is thought to contribute to colon cancer development and metastasis.…”

mentioning

confidence: 99%

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Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

et al. 2016

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EZH2, a member of the polycomb protein group, is an important methyltransferase that is overexpressed in various neoplasms. We found that in small cell B-cell lymphomas, EZH2 is expressed in o 40% of neoplastic cells, with heterogenous signal intensity. In aggressive B-cell lymphomas, 70-100% of tumor cells were positive for EZH2 expression with high signal intensity, which correlated with a high proliferation rate. We investigated the potential signaling molecules that regulate EZH2 overexpression in aggressive B-cell lymphomas and found that 80% of cases of EZH2-positive diffuse large B-cell lymphoma show high p-ERK1/2 expression (average~57% tumor cell positivity). In contrast, only a small percentage of tumor cells (~10%) show p-ERK1/2 expression in Burkitt lymphoma and double hit lymphoma. On average, 91 and 76% of neoplastic cells were positive for MYC expression in Burkitt lymphoma and double hit lymphoma, respectively, while only 20% neoplastic cells were positive for MYC expression in diffuse large B-cell lymphoma. None of the aggressive B-cell lymphomas showed significant p-STAT3 expression in EZH2-overexpressed cases. The correlation of EZH2 expression with aggressive behavior and proliferation rate in B-cell neoplasms suggests that this molecule may function as an oncogenic protein in these neoplasms, with possible regulation by different signaling cascades in different types of aggressive B-cell lymphomas: p-ERK-related signaling in diffuse large B-cell lymphoma, and MYC-related signaling in Burkitt lymphoma and double hit lymphoma. Furthermore, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of aggressive B-cell lymphomas. EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2) and functions as a methytransferase that targets the lysine 27 of histone H3 and controls gene silencing through posttranslational modification. 1 EZH2 is frequently overexpressed in various nonhematological malignancies and functions as an oncogenic protein for tumor cell proliferation, metastasis, and survival. 2 A number of intracytoplasmic oncogenic signaling molecules, transcription factors, and tumor-suppressor miRNAs regulate EZH2 expression in these non-hematological neoplasms. In the triple-negative and ERBB2-overexpressing aggressive subtypes of breast cancer, studies using promoter analysis and in vitro inhibitor methods demonstrated that the MEK/ERK/Elk-1 signaling pathway leads to EZH2 overexpression. 3 In a subset of invasive breast carcinomas and moderately to poorly differentiated non-small cell lung cancers, AKT(Ser473) phosphorylation was closely associated with EZH2 overexpression. 4,5 In prostate and hepatocellular carcinomas, upregulation of MYC protein results in the overexpression of EZH2 through reduction of miR-26a, miR26b, and miR-101. In addition, MYC can directly bind to and activate the EZH2 promoter. [6][7][8]

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

et al. 2016

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“…(21)(22)(23)(24)(25)(26)(27), it would thus be critical to determine whether the targeting of Lin28B by miR-101 plays an important role in NSCLC. To this end, we first examined the function of Lin28B in NSCLC cells.…”

Section: Mir-101 Suppresses Nsclc Tumorigenesis Via Targeting Lin28bmentioning

confidence: 99%

“…For instance, miR-101 has been reported to repress malignant transformation and cancer progression by targeting Mcl-1, Stmn1, Junb, and Cxcr7 in hepatocellular carcinoma (22,27), Mycn in neuroblastoma (25), Ezh2 in prostate cancer (23), Cox2 in colon cancer (21), and Mitf and Ezh2 in melanoma (26). Intriguingly, a recent study found that miR-101 represses TET2 and surprisingly shows an oncogenic potential in malignant hematopoiesis (42).…”

Section: Mir-101 Elicits Its Antitumor Activity Through Targeting Lin28bmentioning

confidence: 99%

“…We showed that IL-1b promoted the proliferation and migration of NSCLC cells and that repression of mir-101 represents an important mechanism of its tumor-promoting activity. Recent studies showed that miR-101 is ubiquitously downregulated in many types of cancers and that it represses malignant transformation and cancer progression by negatively regulating a cohort of oncogenes (21)(22)(23)(24)(25)(26)(27). Nevertheless, the potential role of miR-101 in inflammation-promoted tumorigenesis remained largely unclear.…”

Section: Introductionmentioning

confidence: 99%

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IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

et al. 2014

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Inflammatory stimuli clearly contribute to lung cancer development and progression, but the underlying pathogenic mechanisms are not fully understood. We found that the proinflammatory cytokine IL-1b is dramatically elevated in the serum of patients with non-small cell lung cancer (NSCLC). In vitro studies showed that IL-1b promoted the proliferation and migration of NSCLC cells. Mechanistically, IL-1b acted through the COX2-HIF1a pathway to repress the expression of microRNA-101 (miR-101), a microRNA with an established role in tumor suppression. Lin28B was identified as critical effector target of miR-101 with its repression of Lin28B, a critical aspect of tumor suppression. Overall, IL-1b upregulated Lin28B by downregulating miR-101. Interestingly, cyclooxygenase-2 inhibition by aspirin or celecoxib abrogated IL-1b-mediated repression of miR-101 and IL-1b-mediated activation of Lin28B along with their stimulatory effects on NSCLC cell proliferation and migration. Together, our findings defined an IL-1b-miR-101-Lin28B pathway as a novel regulatory axis of pathogenic inflammatory signaling in NSCLC. Cancer Res; 74(17); 4720-30. Ó2014 AACR.

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Dysregulation of the miR‐194–CUL4B negative feedback loop drives tumorigenesis in non‐small‐cell lung carcinoma

Zou

Lin

et al. 2017

Molecular Oncology

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Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of cancers and represses many tumor suppressors through epigenetic mechanisms. However, the mechanisms by which CUL4B is upregulated remain to be elucidated. Here, we show that CUL4B is upregulated in non‐small‐cell lung carcinoma (NSCLC) tissues and is critically required for cell proliferation and migration in vitro and for xenograft tumor formation in vivo. We found that microRNA‐194 (miR‐194) and CUL4B protein were inversely correlated in cancer specimens and demonstrated that miR‐194 could downregulate CUL4B by directly targeting its 3′‐UTR. We also showed that CUL4B could be negatively regulated by p53 in a miR‐194‐dependent manner. miR‐194 was further shown to attenuate the malignant phenotype of lung cancer cells by downregulating CUL4B. Interestingly, CRL4B also epigenetically represses miR‐194 by catalyzing monoubiquitination at H2AK119 and by coordinating with PRC2 to promote trimethylation at H3K27 at the gene clusters encoding miR‐194. RBX1, another component in CRL4B complex, is also targeted by miR‐194 in NSCLC cells. Our results thus establish a double‐negative feedback loop between miR‐194 and CRL4B, dysregulation of which contributes to tumorigenesis. The function of miR‐194 as a negative regulator of CUL4B has therapeutic implications in lung cancer.

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c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma

Cited by 142 publications

References 43 publications

Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

Dysregulation of the miR‐194–CUL4B negative feedback loop drives tumorigenesis in non‐small‐cell lung carcinoma

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