FHL1 Inhibits the Progression of Colorectal Cancer by Regulating the Wnt/β-Catenin Signaling Pathway

Liu, Yujing; Wang, Chunyan; Cheng, Peiqiu; Zhang, Shengan; Zhou, Wenjun; Xu, Yangxian; Xu, Hanchen; Ji, Guang

doi:10.7150/jca.60543

Cited by 18 publications

(7 citation statements)

References 32 publications

(37 reference statements)

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“…Upregulation of FHL1 has been shown to inhibit cell invasion by increasing RhoGDIß expression in lung cancer . Wnt/β-catenin signaling is a crucial pathway in EMT regulation, and FHL1 has been reported to negatively modulate the Wnt/β-catenin signaling pathway in colorectal cancer . Our study observed that tabersonine upregulated FHL1 protein levels in a dose-dependent manner.…”

Section: Resultssupporting

confidence: 54%

“…45 Wnt/β-catenin signaling is a crucial pathway in EMT regulation, and FHL1 has been reported to negatively modulate the Wnt/β-catenin signaling pathway in colorectal cancer. 46 Our study observed that tabersonine upregulated FHL1 protein levels in a dose-dependent manner. Furthermore, FHL1 knockdown restored the invasive and migratory abilities of the OVC cells after tabersonine treatment, accompanied by the reestablishment of E-cadherin, Ncadherin, and vimentin expression.…”

Section: Identification Of Tabersonine As a Potent Inhibitor Increasi...mentioning

confidence: 48%

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Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial–Mesenchymal Transition in an Ovarian Tumor

Chen,

Yan,

Liu

et al. 2024

J. Nat. Prod.

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Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against the treatment of OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve the therapeutic efficacy of olaparib against OVC is imperative. Our study identified tabersonine, a natural indole alkaloid, for its potential to increase the chemosensitivity of olaparib in OVC. The combined treatment of olaparib and tabersonine synergistically inhibited cell proliferation in OVC cells and suppressed tumor growth in A2780 xenografts. The combined treatment effectively suppressed epithelial−mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, and vimentin and induced DNA damage responses. Integrating quantitative proteomics, FHL1 was identified as a potential regulator to modulate EMT after tabersonine treatment. Increased expression of FHL1 was induced by tabersonine treatment, while downregulation of FHL1 reversed the inhibitory effects of tabersonine on OVC cells by mediating EMT. In vivo findings further reflected that the combined treatment of tabersonine and olaparib significantly inhibited tumor growth and OVC metastasis through upregulation of FHL1. Our findings reveal the role of tabersonine in improving the sensitivity of olaparib in OVC through FHL1-mediated EMT, suggesting that tabersonine holds promise for future application in OVC treatment.

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Section: Resultssupporting

confidence: 54%

Section: Identification Of Tabersonine As a Potent Inhibitor Increasi...mentioning

confidence: 48%

Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial–Mesenchymal Transition in an Ovarian Tumor

Chen,

Yan,

Liu

et al. 2024

J. Nat. Prod.

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“…Current studies have shown that recombinant Helicobacter Pylori aspartate ammonialyase (ASPA) is an effective predictor of prognosis in colorectal cancer patients 52 . Four-and-a-half LIM domains protein (FHL1) has a diagnostic value in microscopic papillary thyroid carcinoma 53 , and it has been reported that FHL1 acts as an inhibitor in colorectal cancer cells [54][55][56] . Receptor activity-modifying protein 3 (RAMP3) is an accessory molecule that forms complexes with and regulates the function of specific G protein-coupled receptors (GPCRs).…”

Section: Discussionmentioning

confidence: 99%

Identidication of novel biomarkers in non-small cell lung cancer using machine learning

Wang

2022

Sci Rep

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Lung cancer is one of the leading causes of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for a large proportion of lung cancer cases, with few diagnostic and therapeutic targets currently available for NSCLC. This study aimed to identify specific biomarkers for NSCLC. We obtained three gene-expression profiles from the Gene Expression Omnibus database (GSE18842, GSE21933, and GSE32863) and screened for differentially expressed genes (DEGs) between NSCLC and normal lung tissue. Enrichment analyses were performed using Gene Ontology, Disease Ontology, and the Kyoto Encyclopedia of Genes and Genomes. Machine learning methods were used to identify the optimal diagnostic biomarkers for NSCLC using least absolute shrinkage and selection operator logistic regression, and support vector machine recursive feature elimination. CIBERSORT was used to assess immune cell infiltration in NSCLC and the correlation between biomarkers and immune cells. Finally, using western blot, small interfering RNA, Cholecystokinin-8, and transwell assays, the biological functions of biomarkers with high predictive value were validated. A total of 371 DEGs (165 up-regulated genes and 206 down-regulated genes) were identified, and enrichment analysis revealed that these DEGs might be linked to the development and progression of NSCLC. ABCA8, ADAMTS8, ASPA, CEP55, FHL1, PYCR1, RAMP3, and TPX2 genes were identified as novel diagnostic biomarkers for NSCLC. Monocytes were the most visible activated immune cells in NSCLC. The knockdown of the TPX2 gene, a biomarker with a high predictive value, inhibited A549 cell proliferation and migration. This study identified eight potential diagnostic biomarkers for NSCLC. Further, the TPX2 gene may be a therapeutic target for NSCLC.

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“…To understand if these gene expression changes are responsible for driving CPSF3 knockdown-mediated phenotypes, we determined the requirement for FHL1 expression in mediating cell proliferation. FHL1 possesses tumor suppressing activity in different cancer types but has not been investigated in the context of PDAC (29–32). We find that silencing of FHL1 , in the context of CPSF3 knockdown, sufficiently rescues the defect in cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, this list included multiple downregulated oncogenes, including SMAD Family Member 6 (SMAD6) and Mitogen-Activated Protein Kinase Kinase 6 We next sought to determine if any of the APA-regulated oncogenes or tumor suppressors were directly responsible for CPSF3 knockdown-mediated attenuation of cell proliferation. We focused on FHL1, as it has been reported to possess tumor suppressor activity in non-PDAC cancers (29)(30)(31)(32), but has no known roles in PDAC biology. FHL1 interacts with transcription factors and signaling proteins, thus modulating gene transcription and signaling pathways (29,33).…”

Section: Cpsf3 Knockdown Dysregulates Global Gene Expression In Pdac ...mentioning

confidence: 99%

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

Alahmari

Chaubey

Tisdale

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options. This potentiates the importance of uncovering novel drug targets. We have discovered global dysregulation of the gene regulatory process alternative polyadenylation (APA) in PDAC. APA is a pre-mRNA processing mechanism that generates mRNAs with distinct 3’ ends, impacting gene expression and protein function. We revealed that APA dysregulation in PDAC drives oncogenic signatures and predicts poor patient outcome. As APA directs widespread gene expression dysregulation across the PDAC patient population, we hypothesized that inhibition of APA has therapeutic potential. APA is controlled by a complex of proteins, including cleavage and polyadenylation specificity factor 3 (CPSF3). CPSF3 is the endonuclease catalyzing mRNA cleavage, and a potentially druggable target. We now find that CPSF3 is highly expressed and associated with poor prognosis in PDAC patients. CPSF3 knockdown decreases PDAC proliferation and clonogenicity in vitro and tumor growth in vivo. We demonstrate that CPSF3 knockdown induces widespread APA alterations of oncogenes and tumor suppressors, and determine the contribution of one of these events to CPSF3-induced cell proliferation phenotype. Furthermore, we find that PDAC, but not non-transformed pancreatic cells, are sensitive to the CPSF3 small molecule inhibitor JTE-607. Mechanistically, JTE-607 impairs replication-dependent histone processing, disrupting nucleosome assembly and destabilizing chromatin structure. Finally, we determine that JTE-607 attenuates cell proliferation by arresting cells in early S-phase of the cell cycle. Altogether, we identify CPSF3 as a druggable target in PDAC and reveal novel mechanisms by which CPSF3 controls cancer cell growth.SignificanceThis work identifies CPSF3 as a potential drug target in pancreatic ductal adenocarcinoma and reveals new mechanisms by which CPSF3 inhibition attenuates PDAC cell proliferation through modulating alternative polyadenylation and histone processing.

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FHL1 Inhibits the Progression of Colorectal Cancer by Regulating the Wnt/β-Catenin Signaling Pathway

Cited by 18 publications

References 32 publications

Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial–Mesenchymal Transition in an Ovarian Tumor

Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial–Mesenchymal Transition in an Ovarian Tumor

Identidication of novel biomarkers in non-small cell lung cancer using machine learning

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

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