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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) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is an oncogene that promotes the malignancy of multiple cancer types. Nonetheless, the interaction between these two factors and significance in lung cancer remains to be determined. Here, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, which leads to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses show that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), which then activates thyroid hormone signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or deiodinase inhibitor disrupts this property. Taken together, our results identify the phosphorylation of AHR by PLK1 as a mechanism leading to the progression of LUAD and provide possible therapeutic interventions for this event.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241973 | GEO | 2023/10/22

REPOSITORIES: GEO

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Project description:The aim of this experiment was to explore transcriptomic changes in the gills of Altantic salmon (Salmo salar) following a model lab based parr smolt transformation from fresh water (FW) to salt water (SW). The process of smoltification (migration from FW to SW) is stimulated by long day photoperiod, which acts on the tissue-specific levels of active thyroid hormone (triiodothyronine, T3) through the expression of thyroid hormone type 2 deiodinase (dio2), responsible for conversion of inactive thyroxine (T4) to T3. To gain insight into the functional significance of dio2 induction, we performed a SW-challenge experiment in which we inhibited dio2 activity by addition of iopanoic acid (IOP) to the SW. We also assessed the ability of co-treatment with T3 to override IOP effects. Juvenile fish maintained in FW were subjected to a standard smolt photoperiod regime known to stimulate smoltification, after which they were randomly allocated to one of the four treatments: SW, SW+IOP, SW+IOP+T3 and FW as a control. Fish (n = 8-10 per treatment) were exposed to these conditions for 6 h and then sacrificed to obtain gill tissue for microarray analysis, carried out using a custom-designed Agilent oligonucleotide microarray platform Salar_2 (one glass slide with 4 x 44K arrays, Agilent design ID: 025520, array design A-MEXP-2065), developed and validated for Atlantic salmon (for details, see specific protocols) . In total, 36 hybridisations were performed on gills from individual fish, with 8-10 replicate fish per treatment. We identified 1939 genes whose expression was significantly increased or decreased by transfer from FW to SW. For a subset of 259 genes, this SW response was abolished if IOP was added to the SW, but maintained if T3 was also present during IOP treatment. This group of genes constitutes a candidate list, for which SW-inducibility appears to be dependent on locally mediated changes in gill T3 availability. The results of this experiment have been submitted for publication in Current Biology and are currently under review.

Project description:Background: Thyroxine (T4) is generally considered to be a pro-hormone that requires conversion to 3,5,3’-triiodothyronine (T3) to exert biological activity. Although evidence suggests that T4 has intrinsic activity, it is questionable if this activity has any physiological relevance. Methods: To answer this question, triple KO mice (Triples) that cannot express the types 1 (D1) and 2 (D2) deiodinase and the Pax8 genes were generated. Thus they lack a thyroid and cannot convert T4 to T3. Triples were injected on alternate days with either vehicle or physiological doses of T4, T3 or T3+T4 from postnatal days 2 to 14. They were euthanized at P15 and RNA-seq was employed to profile gene expression in liver. In another experiment, Pax8KO mice were injected with T3, T4 or T4 +T3, and growth rate and survival to P84 were determined. Results: The growth retardation of Triples was not improved by either T3 or T4 alone but was significantly improved by T4+T3. In liver, T4 significantly regulated the expression of genes that were also regulated by T3, but the proportion of genes that were negatively regulated was higher in mice treated with T4 than with T3. Treatment with T4+T3 identified genes that were regulated synergistically by T3 and T4, and genes that were regulated only by T4+T3. Analysis of these genes revealed enrichment in mechanisms related to cell proliferation and cholesterol physiology, suggesting a unique contribution of T4 to these biological functions. Pax8KO mice all survived to P84 when injected with T4 or T4+T3 but survival rate with T3 was 50% and 10% at 3.5 and 12 weeks of life, respectively. Conclusion: T4 has intrinsic activity in vivo and is critical for survival and growth. At a physiological level, T4 per se can up- or down-regulate many T3 target genes in the neonatal liver. While most of these genes are also regulated by T3, subsets respond exclusively to T4 or demonstrate enhanced or normalized expression only in the presence of both hormones. These studies demonstrate for the first time a complex dependency on both T4 and T3 for normal mammalian growth and development.

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

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