KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling

Li, Jiong; Yu, Bo; Deng, Peng; Cheng, Yingduan; Yu, Yongxin; Kevork, Kareena; Sivakumar, R; Ding, Xiangming; Li, Xinmin; Wang, Cun Yu

doi:10.1038/ncomms15146

Cited by 101 publications

(100 citation statements)

References 70 publications

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“…β-catenin activation has been correlated with progression of human cancers (40) and the functions of CSCs in lung adenocarcinoma (41) and colorectal cancer (42). We previously showed that β-catenin directly regulates the expression of the stem cell marker ALDH1A1 in OC, thus being involved in maintenance of the OCSC phenotype (21).…”

Section: Discussionmentioning

confidence: 99%

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

et al. 2018

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Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.

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Section: Discussionmentioning

confidence: 99%

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

et al. 2018

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“…Given the extreme dosage sensitivity of Dyrk1a and its implication in numerous neurodevelopmental disorders, our finding that Dyrk1a protein levels are regulated in a Mena-dependent manner in axons raises the intriguing possibility that dysregulation of the Mena-RNP complex may contribute to such disorders. Additional mRNAs that are associated with Mena, like the validated targets β-catenin and elavl1 (HuR) are also implicated in multiple developmental processes and pathophysiological conditions (Alami et al, 2014; Blanco et al, 2016; Holland et al, 2013; Krumm et al, 2014; Li et al, 2017; Lu et al, 2014; O’Roak et al, 2012; Wang et al, 2016). Therefore, the Mena-RNP complex may represent a target for the development of novel therapeutic strategies for multiple disease pathologies.…”

Section: Discussionmentioning

confidence: 99%

A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Vidaki

Drees

Saxena

et al. 2017

Neuron

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Summary During neuronal development, local mRNA translation is required for axon guidance and synaptogenesis, and dysregulation of this process contributes to multiple neurodevelopmental and cognitive disorders. However, regulation of local protein synthesis in developing axons remains poorly understood. Here, we uncover a novel role for the actin-regulatory protein Mena in the formation of a ribonucleoprotein complex that involves the RNA-binding proteins HnrnpK, and PCBP1, and regulates local translation of specific mRNAs in developing axons. We find that translation of dyrk1a, a Down Syndrome- and Autism Spectrum Disorders- related gene, is dependent on Mena, both in steady state conditions as well as upon BDNF stimulation. We identify hundreds of additional mRNAs that associate with the Mena complex, suggesting it plays broader role(s) in post-transcriptional gene regulation. Our work establishes a dual role for Mena in neurons, providing a potential link between regulation of actin dynamics and local translation.

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“…During the past decades, most studies on the susceptibility of colorectal cancer have been based on detecting candidate genes, which helps decipher the underlying biological mechanisms of colorectal cancer. These studies mainly focused on genes involved in oncogenic pathways, such as TGF‐β and Wnt . Recent whole‐genome sequencing provides us a perfect method to detect all kinds of genetic alterations potentially associated with various cancers.…”

Section: Introductionmentioning

confidence: 99%

“…These studies mainly focused on genes involved in oncogenic pathways, such as TGF-β and Wnt. 14,15 Recent wholegenome sequencing provides us a perfect method to detect all kinds of genetic alterations potentially associated with various cancers.…”

mentioning

confidence: 99%

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

Wang

Jiang

et al. 2019

Molecular Carcinogenesis

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Genetic factors play important roles in colorectal carcinogenesis. This study was aimed to evaluate the effects of gene expression‐related copy number variations (CNVs) on the risk of colorectal cancer in Chinese. Expression Quantitative Trait Locus (eQTL) mapping was conducted to explore the most regulatable gene expressions by CNVs among the whole genome based on publicly available data. Then a case‐control study was performed to evaluate the associations between copy numbers of the most regulatable genes and colorectal cancer. The influence of the target CNVs on the expression of corresponding gene and protein was verified in colorectal tissue, and the biological effects of these CNVs on cell‐cycle arrest and apoptosis of colon cancer cell lines were further detected. The eQTL revealed the most significant association between CNV of HM3_CNP_342 and gene expressions of human leukocyte antigen (HLA)‐DQA1 and HLA‐DQB1 among the whole genome. The later case‐control study found that amplified HLA‐DQB1 was inversely associated with colorectal cancer risk (odds ratio = 0.73; 95% confidence interval: 0.58‐0.93), especially among those with a family history of cancer. The positive association between amplified HLA‐DQB1 and upregulation of gene and protein was validated in colorectal tissue. In addition, overexpression of HLA‐DQB1 in dendritic cells promoted cell‐cycle arrest and apoptosis of cocultured SW480 and HCT116 cell lines, and vice versa. Our study suggests that the amplified copy number of HLA‐DQB1 is associated with lower risk of colorectal cancer and able to induce the apoptosis of colon cancer cells, which implies the potential of HLA class II in cancer predisposition and immunotherapy.

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KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling

Cited by 101 publications

References 70 publications

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

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