TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance

Tripathi, Veenu; Shin, Jee-Hye; Stuelten, Christina H.; Zhang, Ying E.

doi:10.1038/s41388-018-0655-8

Cited by 78 publications

(72 citation statements)

References 44 publications

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“…ESRP2 also promotes skipping of epithelial-expressed exons in the CTNND1 gene (catenin delta 2, encoding a protein involved in cell adhesion and signalling), while Casodex treatment induces expression of a normally mesenchyme-specific splice isoform (Warzecha et al, 2009b). The Map3k12Δexon12 splice isoform is produced in response to ESRP2 depletion, and is usually expressed in highly metastatic cancer cell lines (Tripathi et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Munkley

Krishnan

et al. 2019

eLife

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Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.

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Section: Discussionmentioning

confidence: 99%

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Munkley

Krishnan

et al. 2019

eLife

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“…Studies have reported that alternative splicing can significantly change the coding region of drug targets and play an important role in the treatment of tumor resistance [ 7 ]. For example, transforming growth factor-β (TGF-β)-induced AS of TAK1 promotes epithelial-mesenchymal transition (EMT) and drug resistance in cancer cells [ 8 ]. SRSF1 regulates the AS of caspase 9 and then influences the chemosensitivity of non-small cell lung cancer (NSCLC) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling

Zheng

Niu

et al. 2021

Aging

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Epithelial splicing regulatory protein 1 (ESRP1) is an RNA-binding protein that regulates alternative splicing of mRNA. ESRP1 plays an important role in chemoresistance of various cancers, including breast cancer, colon cancer and non-small cell lung cancer. However, the role of ESRP1 and its mechanism in small cell lung cancer (SCLC) chemoresistance remains unclear. In this study, we found that ESRP1 is significantly downregulated in SCLC chemo-resistant cells compared with chemo-sensitive cells. Moreover, the expression of ESRP1 was significantly lower in SCLC tissues than that in normal adjacent tissues and positively correlated with overall survival. Overexpression of ESRP1 increased SCLC chemosensitivity, and induced cell apoptosis and cell cycle arrest, whereas knockdown of ESRP1 induced the opposite effects. ESRP1 could inhibit the growth of SCLC in vivo . Through mRNA transcriptome sequencing, we found that ESRP1 regulates coactivator-associated arginine methyltransferase 1 (CARM1) to produce two different transcripts CARM1FL and CARM1ΔE15 by alternative splicing. ESRP1 affects the chemoresistance of SCLC by changing the content of different transcripts of CARM1. Furthermore, CARM1 regulates arginine methylation of Smad7, activates the TGF-β/Smad pathway and induces epithelial-to-mesenchymal transition (EMT), thereby promoting SCLC chemoresistance. Collectively, our study firstly demonstrates that ESRP1 inhibits the TGF-β/Smad signaling pathway by regulating alternative splicing of CARM1, thereby reversing chemoresistance of SCLC. The splicing factor ESRP1 may serve as a new drug resistance marker molecule and a potential therapeutic target in SCLC patients.

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“…signaling pathway [20] . Many researches proved TAK1 kinase triggered TGF-β-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells [21,22] . Choo [23] reported the activation of stress signaling pathways by TAK1 resulted in enhanced migration of colon cancer cells and metastasis to the lung in vivo.…”

Section: Discussionmentioning

confidence: 99%

MALAT1 plays important role in MEK inhibitor, RG7420, on the proliferation and migration of endometrial cancer cell through sponging miR-129-5p/ TAK1

Yuan

Shan

et al. 2020

Preprint

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Background: Endometrial cancer is one of the most common malignancies of the female genital tract. Although the overall five-year survival of EC is much higher than other genital tumor, 25% of the total patients with high risk to develop more aggressive diseases. The metastasis in EC patients is the main cause of death. The MEK inhibitor, which has significant effect on malignant molenoma, lung cancer and so on, has bright future in EC. Method: Here we treated the EC cell line HEC50 and HEC1A with different concentration of RG7420. The CCK8 was used to detecte the cell proliferation rate. Microarray analyzed the difference of LncRNAs in EC cells with or without RG7420. Luciferase reporter assay and RNA immunoprecipitation assay(RIP) were performed to verified the regulation among MALAT1, miR-129-5p and TGF-β-activated kinase 1 (TAK1). QRT-PCR and WB were used to detect the changes in mRNA and protein levels. We also performed ISH to detect the MALAT level in EC paraffin section. Results: We found the RG7420 significantly inhibited the viability and mobility of EC cell lines. Then we analyzed the profile of LncRNA in HEC50 with or without RG7420. We found after treated with IC50 of HEC50, the metastasis-associated lung adenocarcinoma transcript-1(MALAT1) decreased 6.13 times with up-regulation of tumor suppressor miR-129-5p. Our data also provided that MALAT1 may work as endogenous sponge for miR-129-5p. Here we predicted and proved TGF-β-activated kinase 1 (TAK1), encoded by MAP3K7, is the target of miR-129-5p and works as the key factor in metastasis of EC. Meanwhile we compared the MALAT1 level in EC paraffin section by in-situ hybridization. Rerospective analysis assessed the corelation between the MALAT1 level and the clinical characters of EC, MALAT1 is a poor prognostic marker of EC. Furthermore we over-expressed MALAT1 in EC cells, the function of RG7420 was reversed. Conclusion: Taken together, our data uncovered RG7420 inhibited the proliferation and migration of EC cell through MALAT1/miR-129-5p/TAK1 pathway. MALAT1 is a poor prognostic marker of EC.

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TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance

Cited by 78 publications

References 44 publications

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling

MALAT1 plays important role in MEK inhibitor, RG7420, on the proliferation and migration of endometrial cancer cell through sponging miR-129-5p/ TAK1

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