Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer

Zhang, WenQian; Sun, Wei; Qin, Yuan; Wu, CangHao; He, Liang; Zhang, Ting; Shao, Liang; Zhang, Hao; Zhang, Ping

doi:10.1111/jcmm.14311

Cited by 30 publications

(25 citation statements)

References 51 publications

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“…The BRD4 inhibition, by JQ1, which also inhibits c-Myc and induce TTF1 , or by AZD5153, impairs TC cell growth, suggesting that it is critical for thyroid proliferation ( 57 , 58 ). KDM1A is a H3K9 demethylase frequently overexpressed in PTCs and required for migratory and invasive capabilities of PTC cells ( 59 ). TIMP1 has been described as a KDM1A target.…”

Section: Epigenetic Alterations Sustaining Tcscs Origin and Maintenaimentioning

confidence: 99%

“…TIMP1 has been described as a KDM1A target. KDM1A epigenetically silences TIMP1 and subsequently activates MMP9 promoting metastasis and migration ( 59 ). Finally, the enzymatically active component of the PRC complex, EZH2, involved in the regulation of embryonic development and responsible for the trimethylation of lysine 27 on H3 (H3K27me3), leading to silencing of gene transcription, is overexpressed in ATCs ( 60 ).…”

Section: Epigenetic Alterations Sustaining Tcscs Origin and Maintenaimentioning

confidence: 99%

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Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

et al. 2020

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Thyroid tumors are extremely heterogeneous varying from almost benign tumors with good prognosis as papillary or follicular tumors, to the undifferentiated ones with severe prognosis. Recently, several models of thyroid carcinogenesis have been described, mostly hypothesizing a major role of the thyroid cancer stem cell (TCSC) population in both cancer initiation and metastasis formation. However, the cellular origin of TCSC is still incompletely understood. Here, we review the principal epigenetic mechanisms relevant to TCSC origin and maintenance in both well-differentiated and anaplastic thyroid tumors. Specifically, we describe the alterations in DNA methylation, histone modifiers, and microRNAs (miRNAs) involved in TCSC survival, focusing on the potential of targeting aberrant epigenetic modifications for developing novel therapeutic approaches. Moreover, we discuss the bidirectional relationship between TCSCs and immune cells. The cells of innate and adaptive response can promote the TCSC-driven tumorigenesis, and conversely, TCSCs may favor the expansion of immune cells with protumorigenic functions. Finally, we evaluate the role of the tumor microenvironment and the complex cross-talk of chemokines, hormones, and cytokines in regulating thyroid tumor initiation, progression, and therapy refractoriness. The re-education of the stromal cells can be an effective strategy to fight thyroid cancer. Dissecting the genetic and epigenetic landscape of TCSCs and their interactions with tumor microenvironment cells is urgently needed to select more appropriate treatment and improve the outcome of patients affected by advanced differentiated and undifferentiated thyroid cancers.

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Section: Epigenetic Alterations Sustaining Tcscs Origin and Maintenaimentioning

confidence: 99%

Section: Epigenetic Alterations Sustaining Tcscs Origin and Maintenaimentioning

confidence: 99%

Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

et al. 2020

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“…Our study revealed higher KDM1A expression in breast cancer tissue than in normal tissue. High KDM1A expression was associated with aggressive clinical outcomes, such as lymph node involvement, high histological grade, HER2 positivity and lymphatic invasion, which can be found in studies of other cancers [ 35 ]. However, the specific mechanism of how high KDM1A expression affects breast cancer remains poorly understood.…”

Section: Discussionmentioning

confidence: 96%

High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

Kim

Son

Kwon

et al. 2021

JCM

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Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

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“…What's more, further luciferase reporter assay con rmed such regulatory relation. MMP9 is a well-kown tumor promotor and mainly enhances the invasion and metastasis of various tumors [27][28][29]. Moreover, MMP9 also participates in regulating tumor growth [30].…”

Section: Discussionmentioning

confidence: 99%

Mir-483-3p, Mediated by KLF9, Functions as Tumor Suppressor in Testicular Seminoma via Targeting MMP9

Zhang

Ruan

Gao

et al. 2020

Preprint

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Background: Seminoma (SEM) is the most frequent testicular germ cell tumor with a high incidence in young men. The present study aims to explore the function and regulatory mechanism of miR-483-3p in SEM.Methods: RT-qPCR was performed to investigate miR-483-3p levels in SEM tissues. The effect of miR-483-3p on TCam-2 cells was assessed by CCK-8, colony formation, cell migration and invasion assays. Luciferase reporter assays were performed to investigate the interaction between miR-483-3p and MMP9 and then the recovery experiments were performed. Moreover, the potential upstream regulator of miR-483-3p was predicted based on JASPAR database.Results: miR-483-3p was down‐regulated in SEM tissues versus paracancerous normal tissues. The expression level of miR-483-3p was significantly associated with tumor stage by RT-qPCR. Functionally, miR-483-3p over-expression suppressed cell growth, migration and invasion in SEM cell lines. Mechanically, miR-483-3p negatively regulated MMP9 by directly binding to its 3’-UTR. The over-expression of miR-483-3p could reverse the promoting role of MMP9 over-expression on the proliferation, migration and invasion of TCam-2 cells. Moreover, KLF9 was identified as a potential upstream regulator of miR-483-3p and functions as a tumor suppressor.Conclusions: In general, our study suggested that miR-483-3p could inhibit the cell growth, migration and invasion of testicular SEM by targeting MMP9. Moreover, KLF9 is an upstream positive regulator of miR-483-3p and also functions as a tumor suppressor in SEM.

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Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer

Cited by 30 publications

References 51 publications

Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

Mir-483-3p, Mediated by KLF9, Functions as Tumor Suppressor in Testicular Seminoma via Targeting MMP9

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