Lysine demethylase 5B suppresses CC chemokine ligand 14 to promote progression of colorectal cancer through the Wnt/β-catenin pathway

Yan, Guoqiang; Li, Shiquan; Yue, Meng; Li, Chenyao; Kang, Zhenhua

doi:10.1016/j.lfs.2020.118726

Cited by 14 publications

(15 citation statements)

References 26 publications

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“…KYA1797K, a small molecule, inhibits the Wnt/β-catenin signalling pathway [ 41 , 42 ]. We then determined whether KYA1797K suppresses β-catenin-dependent transcriptional activity in AGS and MKN45 cells via miR-3648.…”

Section: Resultsmentioning

confidence: 99%

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

Tang

Pei

et al. 2022

Oncogene

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Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.

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Section: Resultsmentioning

confidence: 99%

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

Tang

Pei

et al. 2022

Oncogene

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“…However, it was also found to be upregulated in other cancers, including bladder, lung, gastric and liver (9,(33)(34)(35). Evidence that KDM5B can drive cancer cell proliferation comes from previous observations that its levels of expression correlated with poor prognosis and that knocking down its expression resulted in the inhibition of cell proliferation in some cancer cell lines, including colorectal and hepatocellular carcinoma lines (36)(37)(38). These data have led to the search for small-molecule weight inhibitors of KDM5B for potential clinical applications (14,16,(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

et al. 2021

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Post-translational modification of histones serve a crucial role in the control of gene transcription. Trimethylation of lysine 4 on histone 3 is associated with transcription activation. There are currently six known methylases and six known demethylases that can control the methylation status of this site. Lysine demethylase 5B (KDM5B) is one such demethylase, which can repress gene expression. In particular KDM5B has been found to be overexpressed in a number of cancer types, and small-molecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knock-out mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔA-T rich interaction domain (ΔARID)-KDM5B strain of mice, which have the ARID domain and five amino acids within the Jumonji (Jmj)N domain spliced out from KDM5B, remain viable and fertile. In the present study, ΔARID-KDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos-1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARID-KDM5B structure compared with that in WT-KDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WT-KDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knock-out mice show varying degrees of lethality, these data suggest that KDM5B serves a crucial function in development in a manner that is independent of its demethylase activity.

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“…Furthermore, we show a higher expression of CCL14 in tumors from women. Suppression of CCL14 has been shown previously to contribute to CRC progression via the Wnt/B-catenin pathway ( 32 ). These findings suggest that increased T cell activity is related to better immune defense against tumor cells in the TME of women compared to men, similar to that of advanced lung cancer ( 33 ).…”

Section: Discussionmentioning

confidence: 97%

An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

Geddes

Ray²,

Nofchissey³

et al. 2022

Front. Oncol.

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Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.

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Lysine demethylase 5B suppresses CC chemokine ligand 14 to promote progression of colorectal cancer through the Wnt/β-catenin pathway

Cited by 14 publications

References 26 publications

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

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