HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Yang, Dong; Cheng, Dazhi; Tu, Qiu; Yang, Huihui; Sun, Bin; Yan, Lei; Dai, Heping; Luo, Jie-Rong; Mao, Bingyu; Cao, Yi; Yu, Xiaoping; Jiang, Hua; Zhao, Xudong

doi:10.7150/thno.24401

Cited by 53 publications

(41 citation statements)

References 49 publications

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“…Together with our observations and ExAC predictions it is likely that mutations predominantly lead to altered function in MM rather than total loss of activity. HUWE1 has generated interest as a potential therapeutic target in a number of malignancies [16,20,31,[35][36][37]. In this study we show that small molecule inhibition or knockdown of HUWE1 effectively reduces the proliferation of MM cells without affecting the viability of healthy BM mononuclear cells.…”

Section: Discussionmentioning

confidence: 54%

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

et al. 2020

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Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM.

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Section: Discussionmentioning

confidence: 54%

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

et al. 2020

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“…P53, a multifunctional transcription factor in cancer progression, participates in the regulation of cell cycle, metabolic pathways, and so on (Stegh, 2012;Fridman & Lowe, 2003;Vogelstein et al, 2000). Studies have found that p53 signaling pathway could induce cancer cell apoptosis by targeting at Bax (Jin et al, 2017), p21, and HIF1 a (Yang et al, 2018) in LUSC. Besides, p53 plays the role in tumor suppression in LUSC via being regulated by other genes, such as miR-223-3p (Luo et al, 2019), which has not been found in the studies of other cancers.…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes associated with progression and prognosis for lung squamous cell carcinoma

Ren

Peng

et al. 2020

PeerJ

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Background Lung squamous cell carcinoma (LUSC) is a major subtype of lung cancer with limited therapeutic options and poor clinical prognosis. Methods Three datasets (GSE19188, GSE33532 and GSE33479) were obtained from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between LUSC and normal tissues were identified by GEO2R, and functional analysis was employed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. Protein–protein interaction (PPI) and hub genes were identified via the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. Hub genes were further validated in The Cancer Genome Atlas (TCGA) database. Subsequently, survival analysis was performed using the Kapla–Meier curve and Cox progression analysis. Based on univariate and multivariate Cox progression analysis, a gene signature was established to predict overall survival. Receiver operating characteristic curve was used to evaluate the prognostic value of the model. Results A total of 116 up-regulated genes and 84 down-regulated genes were identified. These DEGs were mainly enriched in the two pathways: cell cycle and p53 signaling way. According to the degree of protein nodes in the PPI network, 10 hub genes were identified. The mRNA expression levels of the 10 hub genes in LUSC were also significantly up-regulated in the TCGA database. Furthermore, a novel seven-gene signature (FLRT3, PPP2R2C, MMP3, MMP12, CAPN8, FILIP1 and SPP1) from the DEGs was constructed and acted as a significant and independent prognostic signature for LUSC. Conclusions The 10 hub genes might be tightly correlated with LUSC progression. The seven-gene signature might be an independent biomarker with a significant predictive value in LUSC overall survival.

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“…Colony formation assay was performed as described before. 18 Briefly, the base agar containing 0.6% agarose in a 6-well plate was prepared. Next, 1.5 × 10 4 single cells were mixed with 1 mL complete medium supplemented with 0.3% soft agar (Sigma-Aldrich, USA).…”

Section: Colony Formation Assaymentioning

confidence: 99%

<p>Icariin Mitigates the Growth and Invasion Ability of Human Oral Squamous Cell Carcinoma via Inhibiting Toll-Like Receptor 4 and Phosphorylation of NF-κB P65</p>

Lei¹,

Shi

et al. 2020

OTT

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Background: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy worldwide. Icariin (ICA), an active ingredient of flavonoids, has been demonstrated to possess antitumor activity in diverse cancers. Whereas, the role of ICAin OSCC is still unclear. Methods: Herein, we investigated the anti-tumor effects of ICA in vitro and in vivo. CCK-8, colony formation and trans-well assay were used to examined viability, proliferation and invasion in SCC-9 and SCC-15 cell lines, respectively. Next, we tested the expression of tolllike receptor 4 (TLR4) and NF-κB P65 by western blot or immunofluorescence staining. Finally, we constructed a xenograft mice model to investigate the effect of ICA in vivo. Results: In vitro, ICA decreased the human oral squamous cells viability, proliferation and invasion in a concentration-dependent manner. Besides, ICA decreased the phosphorylation level of P65 and down-regulated TLR4 protein. In vivo, compared with control, ICA significantly suppressed the tumor size and weight. In addition, ICA downregulated the levels of Ki67 and VEGF markedly. Dramatically, ICA decreased the phosphorylation level of P65 in tumor tissues. Conclusion: Taken together, ICA could act as a anticancer drug against OSCC to mitigate the growth and invasion ability, the underlying mechanism may due to the down-regulation of TLR4/NF-κB signaling.

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HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Cited by 53 publications

References 49 publications

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

Identification of key genes associated with progression and prognosis for lung squamous cell carcinoma

<p>Icariin Mitigates the Growth and Invasion Ability of Human Oral Squamous Cell Carcinoma via Inhibiting Toll-Like Receptor 4 and Phosphorylation of NF-κB P65</p>

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