The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells

Gobbi, Giulia; Donati, Benedetta; Valle, Ítalo Faria do; Reggiani, Francesca; Torricelli, Federica; Remondini, Daniel; Castellani, Gastone; Ambrosetti, Davide Carlo; Ciarrocchi, Alessia; Sancisi, Valentina

doi:10.1038/s41388-019-0924-1

Cited by 57 publications

(34 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the nucleus, YAP-TAZ-TEAD1 complexes interact with BRD4 and drive the expression of sets of genes involved in cancer transcriptional programs [13]. Furthermore, alterations in some components of the Hippo pathway are determinants of sensitivity to BET protein inhibitors [128]. Some BET protein inhibitors, such as Birabresib, are under clinical trials in different hematologic and solid tumors [129][130][131], but not in HNSCC.…”

Section: Therapeutic Opportunities For Hnscc Targeting the Hippo-yap mentioning

confidence: 99%

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Santos-de-Frutos

Segrelles

Lorz

2019

JCM

View full text Add to dashboard Cite

Head and neck cancer affects the upper aerodigestive tract and is the sixth leading cancer worldwide by incidence and the seventh by cause of death. Despite significant advances in surgery and chemotherapy, molecularly targeted therapeutic options for this type of cancer are scarce and long term survival rates remain low. Recently, comprehensive genomic studies have highlighted the most commonly altered genes and signaling pathways in this cancer. The Hippo-YAP pathway has been identified as a key oncogenic pathway in multiple tumors. Expression of genes controlled by the Hippo downstream transcriptional coactivators YAP (Yes-associated protein 1) and TAZ (WWTR1, WW domain containing transcription regulator 1) is widely deregulated in human cancer including head and neck squamous cell carcinoma (HNSCC). Interestingly, YAP/TAZ signaling might not be as essential for the normal homeostasis of adult tissues as for oncogenic growth, altogether making the pathway an amenable therapeutic target in cancer. Recent advances in the role of Hippo-YAP pathway in HNSCC have provided evidence that genetic alterations frequent in this type of cancer such as PIK3CA (phosphatidylinositide 3-kinase catalytic subunit alpha) overexpression or FAT1 (FAT atypical cadherin 1) functional loss can result in YAP activation. We discuss current therapeutic options targeting this pathway which are currently in use for other tumor types.

show abstract

Section: Therapeutic Opportunities For Hnscc Targeting the Hippo-yap mentioning

confidence: 99%

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Santos-de-Frutos

Segrelles

Lorz

2019

JCM

View full text Add to dashboard Cite

show abstract

“…16 In one study, DLG2 downregulation reversed the suppressing function of miR-23 on the stem cell proliferation of ovarian cancer. 17 The Hippo signaling pathway, on the other hand, controls the size of organs; it is extensively associated with various tumors, including cancer of the liver, [18][19][20] breast, [21][22][23] lung, 24,25 and rectum. 26,27 DLG2 is an upstream effector of the Hippo signaling pathway, yet its function on CRC has never been studied before.…”

Section: Introductionmentioning

confidence: 99%

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Yan

Liu

et al. 2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

This study aimed to investigate the role of circ0106714-miR-942-5p-discs large homolog 2 (DLG2), a novel interactome, in colorectal cancer (CRC). Circ0106714 was found to be the most significantly downregulated circular RNA in CRC using a bioinformatics method, and we researched whether the ability of circ0106714 to sponge miR-942-5p and release DLG2 could affect CRC development via Hippo-YES-associated protein (YAP) signaling. We first employed qRT-PCR and immunoblotting to detect messenger RNA (mRNA) and protein expression, respectively. Live imaging of mice tumor xenografts was then conducted to study the effect of circ0106714 on tumor progression in vivo. Reporter gene assays were subsequently conducted to verify the predicted targeting relationship between circ0106714, miR-942-5p, and DLG2 mRNA in SW480 and HCT116 cell lines. As well as using flow cytometry for both apoptosis and cell cycle profile analyses, CCK-8 and clone foci formation assays were performed to assess cell survival. Wound healing assay and transwell invasion assay were later carried out to evaluate the migration and invasion of the cell lines. Findings revealed that circ0106714 and DLG2 were significantly downregulated, while miR-942-5p was significantly upregulated in human CRC tissues and cell lines. However, circ0106714 upregulation significantly suppressed tumor progression in vivo and inhibited the malignancy phenotypes of tumor cells in vitro by targeting miR-942-5p. Also discovered in this research was that miR-942-5p could directly target DLG2 mRNA, thus enhancing the malignancy phenotypes of CRC cells. We even found that DLG2 overexpression resulted in enhanced phosphorylation of YAP, a critical downstream effector of DLG2. This downstream effector was demonstrated to have a tumor-suppressive capacity in CRC cell lines. In sum, circ0106714 could suppress CRC by sponging miR-942-5p and releasing DLG2, thus promoting YAP phosphorylation.

show abstract

“…Lung cancer is a disease with multiple complex molecular networks underlying its development and progression (1). In recent years, there have been notable advancements in the understanding of the molecular mechanisms involved in lung adenocarcinoma, which has resulted in the identification of numerous targeted drug therapies, which exhibit notably improved survival and prognosis in patients with lung cancer (2-4). Gefitinib, erlotinib and bevacizumab are the most frequently used drugs for treatment of lung cancer (5-7).…”

Section: Introductionmentioning

confidence: 99%

Identification of prognostic markers of lung cancer through bioinformatics analysis and in vitro experiments

et al. 2019

View full text Add to dashboard Cite

Lung cancer is one of the most common types of cancer worldwide. Understanding the molecular mechanisms underlying the development and progression of lung cancer may improve early diagnosis, treatment and prognosis. The aim of the present study was to examine the pathogenesis of lung cancer and to identify potentially novel biomarkers. Gene expression datasets of patients with lung cancer were obtained from the Gene Expression Omnibus. Genes which were most closely associated with lung cancer (core genes) were screened by weighted gene co-expression network analysis. In vitro cell based experiments were further utilized to verify the effects of the core genes on the proliferation of lung cancer cells, adhesion between cells and the matrix, and the associated metabolic pathways. Based on WGCNA screening, two gene modules and five core genes closely associated with lung cancer, including immunoglobulin superfamily member 10 (IGSF10) from the turquoise module, and ribonucleotide reductase regulatory subunit M2, protein regulator of cytokinesis 1, kinesin family member (KIF)14 and KIF2C from the brown module were identified as relevant. Survival analysis and differential gene expression analysis showed that there were significant differences in IGSF10 expression levels between the healthy controls and patients with lung cancer. In patients with lung cancer, IGSF10 expression was decreased, and the overall survival time of patients with lung cancer was significantly shortened. An MTT and colony formation assay showed that IGSF10-knockout significantly increased proliferation of lung cancer cells, and Transwell assays and adhesion experiments further suggested that the adhesion between cells and the matrix was significantly increased in IGSF10-knockout cells. Gene Set Enrichment Analysis showed that the expression level of IGSF10 was significantly associated with the activation of the integrin-β1/focal adhesion kinase (FAK) pathway. Western blotting revealed that knockout of IGSF10 resulted in the activation of the integrin-β1/FAK pathway, as the protein expression levels of integrin-β1, phosphorylated (p)-FAK and p-AKT were significantly upregulated. Activation of the integrin-β1/FAK pathway, following knockout of IGSF10, affected the proliferation and adhesion of lung cancer cells. Therefore, IGSF10 my serve as a potential prognostic marker of lung cancer.

show abstract

The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells

Cited by 57 publications

References 49 publications

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Identification of prognostic markers of lung cancer through bioinformatics analysis and in vitro experiments

Contact Info

Product

Resources

About