Skip to main content
Top
Published in: Digestive Diseases and Sciences 7/2023

Open Access 21-01-2023 | Hepatocellular Carcinoma | Original Article

TEA Domain Transcription Factor 1 Inhibits Ferroptosis and Sorafenib Sensitivity of Hepatocellular Carcinoma Cells

Authors: Hongmin Li, Haitao Lan, Ming Zhang, Fen Zhao, Ning An, Cheng Yi

Published in: Digestive Diseases and Sciences | Issue 7/2023

Login to get access

Abstract

Background

Ferroptosis, as a unique form of cell death, plays crucial negative roles in tumorigenesis and progression. This study aimed to investigate the role and molecular mechanism of TEA domain transcription factor 1 (TEAD1) in HCC and its effect on sorafenib-induced ferroptosis.

Methods

TEAD1 expression was analyzed in HCC tissues using quantitative PCR, and western blot. The effects on cell proliferation, migration and invasion were determined by CCK-8, wound healing and Transwell assays. Intracellular iron, reactive oxygen species (ROS), malondialdehyde (MDA) and GSH measurement was used to assess ferroptosis. Chromatin immunoprecipitation and luciferase reporter gene assays were performed to verify the relationship between TEAD1 and solute carrier family 3 member 2 (SLC3A2). Expression of mTOR, ribosomal protein S6, glutathione peroxidase 4 (GPX4) and SLC3A2 was analyzed by western blot. Tumor xenografts were used assess the effect of TEAD1 on tumor growth in vivo.

Results

TEAD1 was more abundant in HCC compared with normal tissues. Overexpression of TEAD1 enhanced the proliferation, migration, and invasion of HCC cells, while knockdown of TEAD1 inhibited these cell behaviors. Further, TEAD1 inhibited ferroptosis, which was demonstrated by decreased intracellular Fe2+ content, ROS, and MDA levels, and increased GSH activity. Mechnistically, TEAD1 promotes the transcription of SLC3A2 and activates the mTOR signaling. Additionally, silenced TEAD1 restrained tumor growth and enhance sorafenib-induced antitumor activity in vivo.

Conclusions

TEAD1 confers resistance of HCC cells to ferroptosis, thereby promoting the progression of HCC, suggesting the potential value of TEAD1 in the diagnosis and treatment of HCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Hino, K., Iron and liver cancer: an inseparable connection. Adv Sci (Weinh), 2021. Hino, K., Iron and liver cancer: an inseparable connection. Adv Sci (Weinh), 2021.
2.
go back to reference Yanatori I, Hara Y, Nishina S, et al. Ferroptosis in the tumor microenvironment: perspectives for immunotherapy. Febs j 2021;27(9:856–867. Yanatori I, Hara Y, Nishina S, et al. Ferroptosis in the tumor microenvironment: perspectives for immunotherapy. Febs j 2021;27(9:856–867.
3.
go back to reference Yao, X., Li W, Fang D, et al., Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells. 2021:e2100997. Yao, X., Li W, Fang D, et al., Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells. 2021:e2100997.
4.
go back to reference Sun J, Zhou C, Zhao Y, et al. Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biol 2021;41:101942.CrossRefPubMedPubMedCentral Sun J, Zhou C, Zhao Y, et al. Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biol 2021;41:101942.CrossRefPubMedPubMedCentral
5.
go back to reference Wang, Q, Bin C, Xue Q, et al., GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. 2021;12(5):426. Wang, Q, Bin C, Xue Q, et al., GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. 2021;12(5):426.
6.
go back to reference Asperti M, Bellini S, Grillo E, et al. H-ferritin suppression and pronounced mitochondrial respiration make Hepatocellular Carcinoma cells sensitive to RSL3-induced ferroptosis. Free Radic Biol Med 2021;169:294–303.CrossRefPubMed Asperti M, Bellini S, Grillo E, et al. H-ferritin suppression and pronounced mitochondrial respiration make Hepatocellular Carcinoma cells sensitive to RSL3-induced ferroptosis. Free Radic Biol Med 2021;169:294–303.CrossRefPubMed
7.
go back to reference Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res 2021;399(1):112453.CrossRefPubMed Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res 2021;399(1):112453.CrossRefPubMed
8.
go back to reference Huang W, Chen K, Lu Y, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia 2021;23(12):1227–1239.CrossRefPubMedPubMedCentral Huang W, Chen K, Lu Y, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia 2021;23(12):1227–1239.CrossRefPubMedPubMedCentral
9.
go back to reference Li B, Wei S, Yang L, et al. CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma. Front Oncol 2021;11:657723.CrossRefPubMedPubMedCentral Li B, Wei S, Yang L, et al. CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma. Front Oncol 2021;11:657723.CrossRefPubMedPubMedCentral
10.
go back to reference Lin KC, Park HW, Guan KL. Regulation of the Hippo Pathway Transcription Factor TEAD. J Med Chem 2017;42(11):862–872. Lin KC, Park HW, Guan KL. Regulation of the Hippo Pathway Transcription Factor TEAD. J Med Chem 2017;42(11):862–872.
11.
go back to reference Heng BC, Zhang X, Aubel D, et al. An overview of signaling pathways regulating YAP/TAZ activity. 2021;78(2):497–512. Heng BC, Zhang X, Aubel D, et al. An overview of signaling pathways regulating YAP/TAZ activity. 2021;78(2):497–512.
12.
go back to reference Cai X, Yu L, Chen Z et al. Arsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1. Cancer Biomark 2020;28(2):221–230.CrossRefPubMed Cai X, Yu L, Chen Z et al. Arsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1. Cancer Biomark 2020;28(2):221–230.CrossRefPubMed
13.
go back to reference Jiang, N, Zhao L, Zong D, et al. Long non-coding RNA LUADT1 promotes nasopharyngeal carcinoma cell proliferation and invasion by downregulating miR-1207–5p. Bioengineered, 2021. Jiang, N, Zhao L, Zong D, et al. Long non-coding RNA LUADT1 promotes nasopharyngeal carcinoma cell proliferation and invasion by downregulating miR-1207–5p. Bioengineered, 2021.
14.
go back to reference Yin L, Li W, Xu A, et al. SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway. EBioMedicine 2020;51:102596.CrossRefPubMedPubMedCentral Yin L, Li W, Xu A, et al. SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway. EBioMedicine 2020;51:102596.CrossRefPubMedPubMedCentral
15.
go back to reference Gibault F, Sturbaut M, Bailly F, et al. Targeting Transcriptional Enhanced Associate Domains (TEADs). Cell Mol Life Sci 2018;61(12):5057–5072. Gibault F, Sturbaut M, Bailly F, et al. Targeting Transcriptional Enhanced Associate Domains (TEADs). Cell Mol Life Sci 2018;61(12):5057–5072.
16.
go back to reference Lin, W, Zhang T, Ding G, et al. Circular RNA circ CT3 promotes hepatocellular carcinoma progression by regulating the miR-1287-5p/TEAD1/PTCH1/LOX axis. Mol Med Rep, 2021;23(5). Lin, W, Zhang T, Ding G, et al. Circular RNA circ CT3 promotes hepatocellular carcinoma progression by regulating the miR-1287-5p/TEAD1/PTCH1/LOX axis. Mol Med Rep, 2021;23(5).
17.
go back to reference Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 2017;19(8):649–658.CrossRefPubMedPubMedCentral Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 2017;19(8):649–658.CrossRefPubMedPubMedCentral
18.
go back to reference Osman I, He X, Liu J, et al. TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake. Circ Res 2019;124(9):1309–1322.CrossRefPubMedPubMedCentral Osman I, He X, Liu J, et al. TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake. Circ Res 2019;124(9):1309–1322.CrossRefPubMedPubMedCentral
19.
go back to reference Lei G, Zhuang L, Gan B. mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential. Bioessays 2021;43(8):e2100093.CrossRefPubMed Lei G, Zhuang L, Gan B. mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential. Bioessays 2021;43(8):e2100093.CrossRefPubMed
20.
go back to reference Yu MH, Zhang W. TEAD1 enhances proliferation via activating SP1 in colorectal cancer. Biomed Pharmacother 2016;83:496–501.CrossRefPubMed Yu MH, Zhang W. TEAD1 enhances proliferation via activating SP1 in colorectal cancer. Biomed Pharmacother 2016;83:496–501.CrossRefPubMed
21.
go back to reference Chai J, Xu S, Guo F. TEAD1 mediates the oncogenic activities of Hippo-YAP1 signaling in osteosarcoma. Biochem Biophys Res Commun 2017;488(2):297–302.CrossRefPubMed Chai J, Xu S, Guo F. TEAD1 mediates the oncogenic activities of Hippo-YAP1 signaling in osteosarcoma. Biochem Biophys Res Commun 2017;488(2):297–302.CrossRefPubMed
22.
go back to reference Hu X, He B, Zhou L, et al. Elevated TEAD1 Expression is not an Independent Prognosis Factor of Hepatocellular Carcinoma. Clin Lab 2018;64(5):743–748.PubMed Hu X, He B, Zhou L, et al. Elevated TEAD1 Expression is not an Independent Prognosis Factor of Hepatocellular Carcinoma. Clin Lab 2018;64(5):743–748.PubMed
23.
go back to reference Lin Y, Huang G, Jin H, et al. Circular RNA Gprc5a Promotes HCC Progression by Activating YAP1/TEAD1 Signalling Pathway by Sponging miR-1283. Int J Cancer 2020;13:4509–4521. Lin Y, Huang G, Jin H, et al. Circular RNA Gprc5a Promotes HCC Progression by Activating YAP1/TEAD1 Signalling Pathway by Sponging miR-1283. Int J Cancer 2020;13:4509–4521.
24.
go back to reference Liu H, Zhao L, Wang M, et al. FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells. Front Oncol 2022;12:852095.CrossRefPubMedPubMedCentral Liu H, Zhao L, Wang M, et al. FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells. Front Oncol 2022;12:852095.CrossRefPubMedPubMedCentral
25.
go back to reference Fang K, Du S, Shen D, et al. SUFU suppresses ferroptosis sensitivity in breast cancer cells via Hippo/YAP pathway. iScience 2022;25(7):104618. Fang K, Du S, Shen D, et al. SUFU suppresses ferroptosis sensitivity in breast cancer cells via Hippo/YAP pathway. iScience 2022;25(7):104618.
26.
27.
go back to reference Yang WH, Huang Z, Wu J, et al. A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Mol Cancer Res 2020;18(1):79–90.CrossRefPubMed Yang WH, Huang Z, Wu J, et al. A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Mol Cancer Res 2020;18(1):79–90.CrossRefPubMed
28.
go back to reference Yang, W.H. and C.C. Lin, The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. 2021;19(6):1005–1014. Yang, W.H. and C.C. Lin, The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. 2021;19(6):1005–1014.
29.
go back to reference Yang Y, Li X, Wang T, et al. Emerging agents that target signaling pathways in cancer stem cells. 2020;13(1):60. Yang Y, Li X, Wang T, et al. Emerging agents that target signaling pathways in cancer stem cells. 2020;13(1):60.
30.
go back to reference Zhang X, Yu K, Ma L, et al. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. Oncogene 2021;11(12):5650–5674. Zhang X, Yu K, Ma L, et al. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. Oncogene 2021;11(12):5650–5674.
31.
go back to reference Zheng L, Lin CC. DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway. J Hematol Oncol 2021;40(11):2018–2034. Zheng L, Lin CC. DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway. J Hematol Oncol 2021;40(11):2018–2034.
32.
go back to reference Gao, R,Kalathur RKR, Coto-Llerena M, et al., YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. 2021;e14351. Gao, R,Kalathur RKR, Coto-Llerena M, et al., YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. 2021;e14351.
33.
go back to reference Yang WH, Ding CC, Sun T, et al. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep 2019;28(10):2501–2508.e4.CrossRefPubMed Yang WH, Ding CC, Sun T, et al. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep 2019;28(10):2501–2508.e4.CrossRefPubMed
34.
go back to reference Wang, Y. and L. Liu, Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis. 2022. Wang, Y. and L. Liu, Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis. 2022.
35.
go back to reference Liu, J, Wen T, Dong K, et al., TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes. 2021;28(7):2045–2059. Liu, J, Wen T, Dong K, et al., TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes. 2021;28(7):2045–2059.
37.
go back to reference Wei S, Dai M, Zhang C, et al. KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein Cell 2021;12(10):788–809.CrossRefPubMed Wei S, Dai M, Zhang C, et al. KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein Cell 2021;12(10):788–809.CrossRefPubMed
38.
go back to reference Zhang, S, Y.F. Zhou, and J. Cao, mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma. 2021;81(22):5652–5665. Zhang, S, Y.F. Zhou, and J. Cao, mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma. 2021;81(22):5652–5665.
39.
go back to reference Zheng, XFS, Chao X, Wang S, et al., Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy. Cancer Res, 2021. Zheng, XFS, Chao X, Wang S, et al., Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy. Cancer Res, 2021.
40.
go back to reference Zhang, Y, R.V. Swanda, and L. Nie, mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. 2021;12(1):1589. Zhang, Y, R.V. Swanda, and L. Nie, mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. 2021;12(1):1589.
41.
go back to reference Ni J, Chen K, Zhang J, et al. Inhibition of GPX4 or mTOR overcomes resistance to Lapatinib via promoting ferroptosis in NSCLC cells. Biochem Biophys Res Commun 2021;567:154–160.CrossRefPubMed Ni J, Chen K, Zhang J, et al. Inhibition of GPX4 or mTOR overcomes resistance to Lapatinib via promoting ferroptosis in NSCLC cells. Biochem Biophys Res Commun 2021;567:154–160.CrossRefPubMed
Metadata
Title
TEA Domain Transcription Factor 1 Inhibits Ferroptosis and Sorafenib Sensitivity of Hepatocellular Carcinoma Cells
Authors
Hongmin Li
Haitao Lan
Ming Zhang
Fen Zhao
Ning An
Cheng Yi
Publication date
21-01-2023
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 7/2023
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-023-07824-5

Other articles of this Issue 7/2023

Digestive Diseases and Sciences 7/2023 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare