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Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling.

ABSTRACT: Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.

SUBMITTER: Li C

PROVIDER: S-EPMC10662729 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling.

Li Chaohao C Allison Derek B DB He Daheng D Mao Fengyi F Wang Xinyi X Rychahou Piotr P Imam Ibrahim A IA Kong Yifan Y Zhang Qiongsi Q Zhang Yanquan Y Liu Jinghui J Wang Ruixin R Rao Xiongjian X Wu Sai S Evers B Mark BM Shao Qing Q Wang Chi C Li Zhiguo Z Liu Xiaoqi X

PLoS genetics 20231121 11

Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphoryla ...[more]

PMID: 37988371

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Project description:Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.

Project description:Background: Changes in DNA methylation patterns, in which DNA methyltransferases such as DNA methyltransferase 3 alpha (DNMT3a) play important roles, are closely related to the occurrence and development of tumours. However, the role and mechanism of DNMT3a in lung adenocarcinoma (LUAD) remain unknown. The aim of this study was to investigate the potential effect of DNMT3a on LUAD cell proliferation and metastasis and explore the underlying molecular mechanism. Methods: Immunohistochemistry and Kaplan‒Meier survival analysis were used to investigate the relationship between the expression of DNMT3a and histone deacetylase 7 (HDAC7) and the survival, prognosis and clinicopathological features of patients. The effects of DNMT3a on the proliferation and metastasis of LUAD cells were studied in vivo and in vitro. Recombinant lentivirus-mediated in vitro gene overexpression or knockdown, western blotting, Quantitative real-time polymerase chain reaction (qRT‒PCR) and other methods were used in this study to elucidate the potential molecular mechanisms by which DNMT3a promotes LUAD cell proliferation and metastasis. Results: High expression of DNMT3a or HDAC7 was positively correlated with poor prognosis, high AJCC 8th edition stage, and poor tumour differentiation in LUAD patients. LUAD patients with DNMT3a/HDAC7 co-low expression exhibited the worst prognosis. Upregulation of DNMT3a can promote LUAD cell proliferation and metastasis by upregulating HDAC7 and further activating the expression of downstream mediators ZEB1 and c-Myc. Conversely, overexpression of HDAC7 reversed the attenuation of tumour growth and metastasis and the suppression of c-Myc and ZEB1 expression mediated by downregulation of DNMT3a, further indicating the existence of positive feedback regulation between DNMT3a and HDAC7 in LUAD. Conclusion: Our findings first confirmed that DNMT3a acts as a tumour promoter inducing malignant progression of LUAD by upregulating HDAC7 and further inducing upregulation of ZEB1 and c-Myc. Targeting DNMT3a along with HDAC7 might be a promising therapeutic strategy for LUAD.

Project description:Cervical cancer is a leading cause of cancer-related death among women and its recurrence and metastasis poses challenges to treatment. Discoidin domain receptor 1 (DDR1) was associated with cellular migration and invasion in several types of cancers. However, its function in cervical cancer is still unclear. In this study, we found that DDR1 was significantly more expressed in cervical cancer samples than in normal tissues. SRY-Box transcription factor 2 (SOX2), a known oncogene in cervical cancer, showed a positive correlation with DDR1 and regulated DDR1 transcription, contributing to the elevated expression of DDR1 in cervical cancer. Regarding the function of DDR1 in cervical cancer, the overexpression of DDR1 caused an increase in the migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In contrast, cervical cancer cells with reduced DDR1 expression exhibited a lower migration rate, fewer invasive cells, and decreased levels of EMT markers. In vivo, mice injected with cervical cancer cells with overexpressed DDR1 showed more pulmonary metastasis and nodule number. Opposite results were found in mice injected with DDR1 silenced cervical cancer cells. Since DDR1 can cause phosphorylation of downstream targets, a phosphorylation omics was employed to reveal the downstream targets of DDR1, including eukaryotic translation initiation factor 4E binding protein 1 and EPH receptor A2. Furthermore, DDR1 bound directly with Src homology 2 domain of growth factor receptor bound protein 2 (GRB2) which mediated the function of DDR1 in the malignant behaviors of cervical cancer and the phosphorylation of downstream targets. In conclusion, DDR1 binds directly to GRB2 and then affects downstream phosphorylation signals, ultimately exacerbating the metastasis of cervical cancer cells. This work sheds light on the mechanism by which DDR1 functions in cervical cancer cells, providing therapeutic strategy for the treatment of cervical cancer.

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Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling.

Publications

Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling.

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