Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

SETD1A-mediated Methylation of H3K4me3 Inhibits Ferroptosis in Non-small Cell Lung Cancer by Regulating the WTAPP1/WTAP Axis

Author(s): Dao Wang, Yukun Zu, Wei Sun and Xiaowu Fan*

Volume 31, Issue 21, 2024

Published on: 15 August, 2023

Page: [3217 - 3231] Pages: 15

DOI: 10.2174/0929867330666230525143252

Price: $65

Abstract

Introduction: SETD1A is upregulated in non-small cell lung cancer (NSCLC) tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP axis in NSCLC.

Methods: Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation, which is regulated by multiple cellular metabolic pathways, including REDOX homeostasis, iron metabolism, mitochondrial activity and metabolism of amino acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were measured in vitro, and NSCLC cell behaviors were assessed. SETD1A-mediated H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor growth in vivo were verified in nude mouse models.

Results: SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis. WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis. Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude mice through the WTAPP1/WTAP axis.

Conclusion: SETD1A amplified WTAP expression through WTAPP1 upregulation by mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC cell proliferation and migration and inhibiting ferroptosis.

« Previous Next »
[1]
Nasim, F.; Sabath, B.F.; Eapen, G.A. Lung cancer. Med. Clin. North Am., 2019, 103(3), 463-473.
[http://dx.doi.org/10.1016/j.mcna.2018.12.006] [PMID: 30955514]
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
VanderLaan, P.A.; Roy-Chowdhuri, S. Current and future trends in non–small cell lung cancer biomarker testing: The American experience. Cancer Cytopathol., 2020, 128(9), 629-636.
[http://dx.doi.org/10.1002/cncy.22313] [PMID: 32885913]
[4]
Duma, N.; Santana-Davila, R.; Molina, J.R. Non–small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin. Proc., 2019, 94(8), 1623-1640.
[http://dx.doi.org/10.1016/j.mayocp.2019.01.013] [PMID: 31378236]
[5]
Schegoleva, A.A.; Khozyainova, A.A.; Fedorov, A.A.; Gerashchenko, T.S.; Rodionov, E.O.; Topolnitsky, E.B.; Shefer, N.A.; Pankova, O.V.; Durova, A.A.; Zavyalova, M.V.; Perelmuter, V.M.; Denisov, E.V. Prognosis of different types of non-small cell lung cancer progression: Current state and perspectives. Cell. Physiol. Biochem., 2021, 55(S2), 29-48.
[http://dx.doi.org/10.33594/000000340] [PMID: 33687819]
[6]
Arbour, K.C.; Riely, G.J. Systemic therapy for locally advanced and metastatic non–small cell lung cancer. JAMA, 2019, 322(8), 764-774.
[http://dx.doi.org/10.1001/jama.2019.11058] [PMID: 31454018]
[7]
Chen, X.; Li, J.; Kang, R.; Klionsky, D.J.; Tang, D. Ferroptosis: Machinery and regulation. Autophagy, 2021, 17(9), 2054-2081.
[http://dx.doi.org/10.1080/15548627.2020.1810918] [PMID: 32804006]
[8]
Tsikas, D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal. Biochem., 2017, 524, 13-30.
[http://dx.doi.org/10.1016/j.ab.2016.10.021] [PMID: 27789233]
[9]
Fujii, J.; Homma, T.; Osaki, T. Superoxide radicals in the execution of cell death. Antioxidants, 2022, 11(3), 501.
[http://dx.doi.org/10.3390/antiox11030501] [PMID: 35326151]
[10]
Gao, M.; Monian, P.; Pan, Q.; Zhang, W.; Xiang, J.; Jiang, X. Ferroptosis is an autophagic cell death process. Cell Res., 2016, 26(9), 1021-1032.
[http://dx.doi.org/10.1038/cr.2016.95] [PMID: 27514700]
[11]
Yang, W.S.; SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A. Regulation of ferroptotic cancer cell death by GPX4. Cell, 2014, 156(1-2), 317-331.
[http://dx.doi.org/10.1016/j.cell.2013.12.010] [PMID: 24439385]
[12]
Zhang, Y.; Liu, X.; Zeng, L.; Zhao, X.; Chen, Q.; Pan, Y.; Bai, Y.; Shao, C.; Zhang, J. Exosomal protein angiopoietin-like 4 mediated radioresistance of lung cancer by inhibiting ferroptosis under hypoxic microenvironment. Br. J. Cancer, 2022, 127(10), 1760-1772.
[http://dx.doi.org/10.1038/s41416-022-01956-7] [PMID: 36050447]
[13]
Zou, J.; Wang, L.; Tang, H.; Liu, X.; Peng, F.; Peng, C. Ferroptosis in non-small cell lung cancer: Progression and therapeutic potential on it. Int. J. Mol. Sci., 2021, 22(24), 13335.
[http://dx.doi.org/10.3390/ijms222413335] [PMID: 34948133]
[14]
Feng, Y.; Xu, J.; Shi, M.; Liu, R.; Zhao, L.; Chen, X.; Li, M.; Zhao, Y.; Chen, J.; Du, W.; Liu, P. COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism. Cell Death Dis., 2022, 13(11), 988.
[http://dx.doi.org/10.1038/s41419-022-05430-3] [PMID: 36418320]
[15]
Wang, L.; Fu, H.; Song, L.; Wu, Z.; Yu, J.; Guo, Q.; Chen, C.; Yang, X.; Zhang, J.; Wang, Q.; Duan, Y.; Yang, Y. Overcoming AZD9291 resistance and metastasis of NSCLC via ferroptosis and multitarget interference by nanocatalytic sensitizer plus AHP-DRI-12. Small, 2023, 19(4), 2204133.
[http://dx.doi.org/10.1002/smll.202204133] [PMID: 36420659]
[16]
Zhao, X.; Cui, L.; Zhang, Y.; Guo, C.; Deng, L.; Wen, Z.; Lu, Z.; Shi, X.; Xing, H.; Liu, Y.; Zhang, Y. Screening for potential therapeutic agents for non-small cell lung cancer by targeting ferroptosis. Front. Mol. Biosci., 2022, 9, 917602.
[http://dx.doi.org/10.3389/fmolb.2022.917602] [PMID: 36203872]
[17]
Van Den Broeck, A.; Ozenne, P.; Eymin, B.; Gazzeri, S. Lung cancer. Cell Adhes. Migr., 2010, 4(1), 107-113.
[http://dx.doi.org/10.4161/cam.4.1.10885] [PMID: 20139698]
[18]
Weinhold, B. Epigenetics: The science of change. Environ. Health Perspect., 2006, 114(3), A160-A167.
[http://dx.doi.org/10.1289/ehp.114-a160] [PMID: 16507447]
[19]
Flavahan, W.A.; Gaskell, E.; Bernstein, B.E. Epigenetic plasticity and the hallmarks of cancer. Science, 2017, 357(6348), eaal2380.
[http://dx.doi.org/10.1126/science.aal2380] [PMID: 28729483]
[20]
Piunti, A.; Shilatifard, A. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science, 2016, 352(6290), aad9780.
[http://dx.doi.org/10.1126/science.aad9780] [PMID: 27257261]
[21]
Marques, A.C.; Hughes, J.; Graham, B.; Kowalczyk, M.S.; Higgs, D.R.; Ponting, C.P. Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs. Genome Biol., 2013, 14(11), R131.
[http://dx.doi.org/10.1186/gb-2013-14-11-r131] [PMID: 24289259]
[22]
Batie, M.; Rocha, S. Gene transcription and chromatin regulation in hypoxia. Biochem. Soc. Trans., 2020, 48(3), 1121-1128.
[http://dx.doi.org/10.1042/BST20191106] [PMID: 32369557]
[23]
Shilatifard, A. The COMPASS family of histone H3K4 methylases: Mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem., 2012, 81(1), 65-95.
[http://dx.doi.org/10.1146/annurev-biochem-051710-134100] [PMID: 22663077]
[24]
Wang, H.; Fan, Z.; Shliaha, P.V.; Miele, M.; Hendrickson, R.C.; Jiang, X.; Helin, K. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature, 2023, 615(7951), 339-348.
[http://dx.doi.org/10.1038/s41586-023-05780-8] [PMID: 36859550]
[25]
Lauberth, S.M.; Nakayama, T.; Wu, X.; Ferris, A.L.; Tang, Z.; Hughes, S.H.; Roeder, R.G. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell, 2013, 152(5), 1021-1036.
[http://dx.doi.org/10.1016/j.cell.2013.01.052] [PMID: 23452851]
[26]
Vermeulen, M.; Eberl, H.C.; Matarese, F.; Marks, H.; Denissov, S.; Butter, F.; Lee, K.K.; Olsen, J.V.; Hyman, A.A.; Stunnenberg, H.G.; Mann, M. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell, 2010, 142(6), 967-980.
[http://dx.doi.org/10.1016/j.cell.2010.08.020] [PMID: 20850016]
[27]
Wang, R.; Liu, J.; Li, K.; Yang, G.; Chen, S.; Wu, J.; Xie, X.; Ren, H.; Pang, Y. An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development. J. Exp. Clin. Cancer Res., 2021, 40(1), 318.
[http://dx.doi.org/10.1186/s13046-021-02119-x] [PMID: 34645486]
[28]
Kang, J.Y.; Park, J.W.; Hwang, Y.; Hahm, J.Y.; Park, J.; Park, K.S.; Seo, S.B. The H3K4 methyltransferase SETD1A is required for proliferation of non-small cell lung cancer cells by promoting S-phase progression. Biochem. Biophys. Res. Commun., 2021, 561, 120-127.
[http://dx.doi.org/10.1016/j.bbrc.2021.05.026] [PMID: 34023776]
[29]
Jin, M.L.; Kim, Y.W.; Jin, H.L.; Kang, H.; Lee, E.K.; Stallcup, M.R.; Jeong, K.W. Aberrant expression of SETD1A promotes survival and migration of estrogen receptor α-positive breast cancer cells. Int. J. Cancer, 2018, 143(11), 2871-2883.
[http://dx.doi.org/10.1002/ijc.31853] [PMID: 30191958]
[30]
Hoshii, T.; Cifani, P.; Feng, Z.; Huang, C.H.; Koche, R.; Chen, C.W.; Delaney, C.D.; Lowe, S.W.; Kentsis, A.; Armstrong, S.A. A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response. Cell, 2018, 172(5), 1007-1021.e17.
[http://dx.doi.org/10.1016/j.cell.2018.01.032] [PMID: 29474905]
[31]
Salz, T.; Li, G.; Kaye, F.; Zhou, L.; Qiu, Y.; Huang, S. hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells. Cancer Res., 2014, 74(3), 775-786.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-1400] [PMID: 24247718]
[32]
Wu, J.; Chai, H.; Xu, X.; Yu, J.; Gu, Y. Histone methyltransferase SETD1A interacts with HIF1α to enhance glycolysis and promote cancer progression in gastric cancer. Mol. Oncol., 2020, 14(6), 1397-1409.
[http://dx.doi.org/10.1002/1878-0261.12689] [PMID: 32291851]
[33]
Wang, L.; Ma, L.; Xu, F.; Zhai, W.; Dong, S.; Yin, L.; Liu, J.; Yu, Z. Role of long non-coding RNA in drug resistance in non-small cell lung cancer. Thorac. Cancer, 2018, 9(7), 761-768.
[http://dx.doi.org/10.1111/1759-7714.12652] [PMID: 29726094]
[34]
Fang, C.; Wang, L.; Gong, C.; Wu, W.; Yao, C.; Zhu, S. Long non-coding RNAs: How to regulate the metastasis of non–small-cell lung cancer. J. Cell. Mol. Med., 2020, 24(6), 3282-3291.
[http://dx.doi.org/10.1111/jcmm.15054] [PMID: 32048814]
[35]
Herrera-Solorio, A.M.; Peralta-Arrieta, I.; Armas López, L.; Hernández-Cigala, N.; Mendoza Milla, C.; Ortiz Quintero, B.; Catalán Cárdenas, R.; Pineda Villegas, P.; Rodríguez Villanueva, E.; Trejo Iriarte, C.G.; Zúñiga, J.; Arrieta, O.; Ávila-Moreno, F. LncRNA SOX2-OT regulates AKT/ERK and SOX2/GLI-1 expression, hinders therapy, and worsens clinical prognosis in malignant lung diseases. Mol. Oncol., 2021, 15(4), 1110-1129.
[http://dx.doi.org/10.1002/1878-0261.12875] [PMID: 33433063]
[36]
Zhang, L.; Jin, C.; Yang, G.; Wang, B.; Hua, P.; Zhang, Y. LncRNA WTAPP1 promotes cancer cell invasion and migration in NSCLC by downregulating lncRNA HAND2-AS1. BMC Pulm. Med., 2020, 20(1), 153.
[http://dx.doi.org/10.1186/s12890-020-01180-0] [PMID: 32473628]
[37]
Weng, L.; Qiu, K.; Gao, W.; Shi, C.; Shu, F. LncRNA PCGEM1 accelerates non-small cell lung cancer progression via sponging miR-433-3p to upregulate WTAP. BMC Pulm. Med., 2020, 20(1), 213.
[http://dx.doi.org/10.1186/s12890-020-01240-5] [PMID: 32787827]
[38]
Cheng, H.; Wang, S.J.; Li, Z.; Ma, Y.; Song, Y.R. ING2-WTAP is a potential therapeutic target in non-small cell lung cancer. Biochem. Biophys. Res. Commun., 2022, 605, 31-38.
[http://dx.doi.org/10.1016/j.bbrc.2022.02.041] [PMID: 35306362]
[39]
Li, B.Q.; Huang, S.; Shao, Q.Q.; Sun, J.; Zhou, L.; You, L.; Zhang, T.P.; Liao, Q.; Guo, J.C.; Zhao, Y.P. WT1-associated protein is a novel prognostic factor in pancreatic ductal adenocarcinoma. Oncol. Lett., 2017, 13(4), 2531-2538.
[http://dx.doi.org/10.3892/ol.2017.5784] [PMID: 28454430]
[40]
Zhang, J.; Tsoi, H.; Li, X.; Wang, H.; Gao, J.; Wang, K.; Go, M.Y.Y.; Ng, S.C.; Chan, F.K.L.; Sung, J.J.Y.; Yu, J. Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP–WT1–TBL1 axis. Gut, 2016, 65(9), 1482-1493.
[http://dx.doi.org/10.1136/gutjnl-2014-308614] [PMID: 26071132]
[41]
Deng, J.; Zhang, J.; Ye, Y.; Liu, K.; Zeng, L.; Huang, J.; Pan, L.; Li, M.; Bai, R.; Zhuang, L.; Huang, X.; Wu, G.; Wei, L.; Zheng, Y.; Su, J.; Zhang, S.; Chen, R.; Lin, D.; Zheng, J. N6 -methyladenosine–Mediated upregulation of WTAPP1 promotes WTAP translation and Wnt signaling to facilitate pancreatic cancer progression. Cancer Res., 2021, 81(20), 5268-5283.
[http://dx.doi.org/10.1158/0008-5472.CAN-21-0494] [PMID: 34362795]
[42]
Tong, X.; Su, P.; Yang, H.; Chi, F.; Shen, L.; Feng, X.; Jiang, H.; Zhang, X.; Wang, Z. MicroRNA‑598 inhibits the proliferation and invasion of non‑small cell lung cancer cells by directly targeting ZEB2. Exp. Ther. Med., 2018, 16(6), 5417-5423.
[http://dx.doi.org/10.3892/etm.2018.6825] [PMID: 30542503]
[43]
Tan, Z.; Wang, W.; Peng, J.; Zhou, Z.; Pan, J.; Peng, A.; Cao, H.; Fan, W. Impact of amarogentin on gastric carcinoma cell multiplication, apoptosis and migration via circKIF4A/miR-152-3p. J. Immunol. Res., 2022, 2022, 1-9.
[http://dx.doi.org/10.1155/2022/2156204] [PMID: 35747689]
[44]
Sayegh, J.; Cao, J.; Zou, M.R.; Morales, A.; Blair, L.P.; Norcia, M.; Hoyer, D.; Tackett, A.J.; Merkel, J.S.; Yan, Q. Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J. Biol. Chem., 2013, 288(13), 9408-9417.
[http://dx.doi.org/10.1074/jbc.M112.419861] [PMID: 23408432]
[45]
Hu, A.; Hong, F.; Li, D.; Jin, Y.; Kon, L.; Xu, Z.; He, H.; Xie, Q. Long non-coding RNA ROR recruits histone transmethylase MLL1 to up-regulate TIMP3 expression and promote breast cancer progression. J. Transl. Med., 2021, 19(1), 95.
[http://dx.doi.org/10.1186/s12967-020-02682-5] [PMID: 33653378]
[46]
Schabath, M.B.; Cote, M.L. Cancer progress and priorities: Lung cancer. Cancer Epidemiol. Biomarkers Prev., 2019, 28(10), 1563-1579.
[http://dx.doi.org/10.1158/1055-9965.EPI-19-0221] [PMID: 31575553]
[47]
Bajbouj, K.; Al-Ali, A.; Ramakrishnan, R.K.; Saber-Ayad, M.; Hamid, Q. Histone modification in NSCLC: Molecular mechanisms and therapeutic targets. Int. J. Mol. Sci., 2021, 22(21), 11701.
[http://dx.doi.org/10.3390/ijms222111701] [PMID: 34769131]
[48]
Du, M.; Gong, P.; Zhang, Y.; Liu, Y.; Liu, X.; Zhang, F.; Wang, X. Histone methyltransferase SETD1A participates in lung cancer progression. Thorac. Cancer, 2021, 12(16), 2247-2257.
[http://dx.doi.org/10.1111/1759-7714.14065] [PMID: 34219384]
[49]
Guo, F.; Guo, R.; Zhang, L. Downregulation of lncRNA FOXD2-AS1 confers radiosensitivity to gastric cancer cells via miR-1913/SETD1A axis. Cytogenet. Genome Res., 2022, 162(1-2), 10-27.
[http://dx.doi.org/10.1159/000522653] [PMID: 35354145]
[50]
Ishii, T.; Akiyama, Y.; Shimada, S.; Kabashima, A.; Asano, D.; Watanabe, S.; Ishikawa, Y.; Ueda, H.; Akahoshi, K.; Ogawa, K.; Ono, H.; Kudo, A.; Tanabe, M.; Tanaka, S. Identification of a novel target of SETD1A histone methyltransferase and the clinical significance in pancreatic cancer. Cancer Sci., 2022.
[PMID: 36271761]
[51]
Matsumura, Y.; Nakaki, R.; Inagaki, T.; Yoshida, A.; Kano, Y.; Kimura, H.; Tanaka, T.; Tsutsumi, S.; Nakao, M.; Doi, T.; Fukami, K.; Osborne, T.F.; Kodama, T.; Aburatani, H.; Sakai, J. H3K4/H3K9me3 Bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Mol. Cell, 2015, 60(4), 584-596.
[http://dx.doi.org/10.1016/j.molcel.2015.10.025] [PMID: 26590716]
[52]
Yang, X; Mei, C; Raza, SHA; Ma, X; Wang, J; Du, J; Zan, L Interactive regulation of DNA demethylase gene TET1 and m(6)A methyltransferase gene METTL3 in myoblast differentiation. Int J Biol Macromol, 2022, 223(Pt A), 916-930.
[53]
Yang, J.; Peng, S.; Zhang, K. ARL4C depletion suppresses the resistance of ovarian cancer to carboplatin by disrupting cholesterol transport and autophagy via notch-RBP-Jκ-H3K4Me3-OSBPL5. Hum. Exp. Toxicol., 2022, 41
[http://dx.doi.org/10.1177/09603271221135064] [PMID: 36366750]
[54]
Shi, X.Y.; Lin, J.J.; Ge, X.J.; Shi, Y. LncRNA WTAPP1 promotes proliferation of laryngeal carcinoma cells through regulating microRNA-592. Eur. Rev. Med. Pharmacol. Sci., 2020, 24(18), 9532-9540.
[PMID: 33015795]
[55]
Li, Q.; Wang, C.; Dong, W.; Su, Y.; Ma, Z. WTAP facilitates progression of endometrial cancer via CAV-1/NF-κB axis. Cell Biol. Int., 2021, 45(6), 1269-1277.
[http://dx.doi.org/10.1002/cbin.11570] [PMID: 33559954]
[56]
Ni, L.; Bai, R.; Zhou, Q.; Yuan, C.; Zhou, L.T.; Wu, X. The correlation between ferroptosis and m6A methylation in patients with acute kidney injury. Kidney Blood Press. Res., 2022, 47(8), 523-533.
[http://dx.doi.org/10.1159/000524900] [PMID: 35569444]
[57]
Jin, M.L.; Yang, L.; Jeong, K.W. SETD1A-SOX2 axis is involved in tamoxifen resistance in estrogen receptor α-positive breast cancer cells. Theranostics, 2022, 12(13), 5761-5775.
[http://dx.doi.org/10.7150/thno.72599] [PMID: 35966598]
[58]
Chen, Y.; Peng, C.; Chen, J.; Chen, D.; Yang, B.; He, B.; Hu, W.; Zhang, Y.; Liu, H.; Dai, L.; Xie, H.; Zhou, L.; Wu, J.; Zheng, S. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol. Cancer, 2019, 18(1), 127.
[http://dx.doi.org/10.1186/s12943-019-1053-8] [PMID: 31438961]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy