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On-line Access: 2022-10-12

Received: 2022-03-18

Revision Accepted: 2022-06-02

Crosschecked: 2022-10-13

Cited: 0

Clicked: 279

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Hailong PIAO

https://orcid.org/0000-0001-7451-0386

Chundong GU

https://orcid.org/0000-0002-2981-6578

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Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.10 P.863-875

http://doi.org/10.1631/jzus.B2200144


UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis


Author(s):  Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU

Affiliation(s):  Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; more

Corresponding email(s):   guchundong@dmu.edu.cn, hpiao@dicp.ac.cn

Key Words:  Up-frameshift 1 (UPF1), Activating transcription factor 4 (ATF4), Amino acid metabolism, Lung adenocarcinoma


Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU. UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis[J]. Journal of Zhejiang University Science B, 2022, 23(10): 863-875.

@article{title="UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis",
author="Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU",
journal="Journal of Zhejiang University Science B",
volume="23",
number="10",
pages="863-875",
year="2022",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200144"
}

%0 Journal Article
%T UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis
%A Lei FANG
%A Huan QI
%A Peng WANG
%A Shiqing WANG
%A Tianjiao LI
%A Tian XIA
%A Hailong PIAO
%A Chundong GU
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 10
%P 863-875
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200144

TY - JOUR
T1 - UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis
A1 - Lei FANG
A1 - Huan QI
A1 - Peng WANG
A1 - Shiqing WANG
A1 - Tianjiao LI
A1 - Tian XIA
A1 - Hailong PIAO
A1 - Chundong GU
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 10
SP - 863
EP - 875
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200144


Abstract: 
up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.

UPF1通过调控eIF2α-ATF4通路提高细胞内氨基酸水平促进肺腺癌增殖

房磊1,齐欢2,王鹏1,王世晴1,李天娇1,夏天2,朴海龙2,顾春东1
1大连医科大学附属第一医院胸外科,大连市肺癌诊疗中心,中国大连,116011
2中国科学院分析化学分离科学重点实验室,中国科学院大连化学物理研究所,中国大连,116023
目的:UPF1是调节无义介导的mRNA降解的核心因子,参与多种肿瘤进展相关分子通路的调节,其在肺腺癌氨基酸代谢中的作用尚不清楚。
方法和结果:本研究通过结合生物信息学和代谢组学,分析发现UPF1与肺腺癌中部分氨基酸代谢通路显著相关,证实UPF1敲低后可显著抑制氨基酸代谢重编程核心蛋白ATF4的表达及eIF2α-Ser51位点的磷酸化水平,且UPF1通过调控ATF4蛋白增加肺腺癌细胞的氨基酸水平进而促进细胞增殖。在临床患者样本数据库中,肺腺癌组织中UPF1的mRNA水平表达异常,UPF1和ATF4均高表达的肺腺癌患者有着较差的总生存期。
结论:本研究表明,UPF1是肿瘤氨基酸代谢重编程的潜在调控因子,可作为肺腺癌治疗的新靶点。

关键词:UPF1;ATF4;氨基酸;肺腺癌

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Abdel-WahabAF, MahmoudW, Al-HarizyRM, 2019. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res, 150:104511.

[2]AdamsCM, 2007. Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids. J Biol Chem, 282(23):16744-16753.

[3]AmeriK, HarrisAL, 2008. Activating transcription factor 4. Int J Biochem Cell Biol, 40(1):14-21.

[4]BaiXP, NiJ, BeretovJ, et al., 2021. Activation of the eIF2α/ATF4 axis drives triple-negative breast cancer radioresistance by promoting glutathione biosynthesis. Redox Biol, 43:101993.

[5]B’chirW, MaurinAC, CarraroV, et al., 2013. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res, 41(16):7683-7699.

[6]BoroughsLK, DeBerardinisRJ, 2015. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol, 17(4):351-359.

[7]CaoYH, 2019. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest, 129(8):3006-3017.

[8]ChangL, LiCC, GuoT, et al., 2016. The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma. J Exp Clin Cancer Res, 35:8.

[9]ChenBL, WangHM, LinXS, et al., 2021. UPF1: a potential biomarker in human cancers. Front Biosci (Landmark Ed), 26(5):76-84.

[10]ChenPH, CaiL, HuffmanK, et al., 2019. Metabolic diversity in human non-small cell lung cancer cells. Mol Cell, 76(5):838-851.e5.

[11]DehecqM, DecourtyL, NamaneA, et al., 2018. Nonsense-mediated mRNA decay involves two distinct Upf1-bound complexes. EMBO J, 37(21):e99278.

[12]DiasAS, AlmeidaCR, HelgueroLA, et al., 2019. Metabolic crosstalk in the breast cancer microenvironment. Eur J Cancer, 121:154-171.

[13]FerlayJ, SoerjomataramI, DikshitR, et al., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 136(5):E359-E386.

[14]GeorgoudakiAM, ProkopecKE, BouraVF, et al., 2016. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep, 15(9):2000-2011.

[15]GuoX, WangAM, WangW, et al., 2021. HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple-negative breast cancer. Mol Oncol, 15(2):642-656.

[16]GwinnDM, LeeAG, Briones-Martin-Del-CampoM, et al., 2018. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell, 33(1):91‍-‍107.E6.

[17]HaiT, CurranT, 1991. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA, 88(9):3720-3724.

[18]HanSH, CaoDD, ShaJ, et al., 2020. LncRNA ZFPM2-AS1 promotes lung adenocarcinoma progression by interacting with UPF1 to destabilize ZFPM2. Mol Oncol, 14(5):1074-1088.

[19]HanahanD, WeinbergRA, 2011. Hallmarks of cancer: the next generation. Cell, 144(5):646-674.

[20]KawauchiK, ArakiK, TobiumeK, et al., 2008. p53 regulates glucose metabolism through an IKK‍-NF-‍κB pathway and inhibits cell transformation. Nat Cell Biol, 10(5):611-618.

[21]KrishnamoorthyGP, DavidsonNR, LeachSD, et al., 2019. EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov, 9(2):264-281.

[22]KurosakiT, PoppMW, MaquatLE, 2019. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol, 20(7):406-420.

[23]LeeJV, CarrerA, ShahS, et al., 2014. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab, 20(2):306-319.

[24]LiXZ, YanXH, 2019. Sensors for the mTORC1 pathway regulated by amino acids. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(9):699-712.

[25]LiL, GengY, FengR, et al., 2017. The human RNA surveillance factor UPF1 modulates gastric cancer progression by targeting long non-coding RNA MALAT1. Cell Physiol Biochem, 42(6):2194-2206.

[26]LiZY, ZhangHF, 2016. Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci, 73(2):377-392.

[27]LieuEL, NguyenT, RhyneS, et al., 2020. Amino acids in cancer. Exp Mol Med, 52(1):15-30.

[28]LiuC, KaramR, ZhouYQ, et al., 2014. The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat Med, 20(6):596-598.

[29]Lykke-AndersenS, JensenTH, 2015. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol, 16(11):665-677.

[30]MossmannD, ParkS, HallMN, 2018. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer, 18(12):744-757.

[31]NewmanAC, MaddocksODK, 2017. One-carbon metabolism in cancer. Br J Cancer, 116(12):1499-1504.

[32]NicholsonP, YepiskoposyanH, MetzeS, et al., 2010. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci, 67(5):677-700.

[33]PeiCL, FeiKL, YuanXY, et al., 2019. LncRNA DANCR aggravates the progression of ovarian cancer by downregulating UPF1. Eur Rev Med Pharmacol Sci, 23(24):10657-10663.

[34]PengYY, YangH, LiS, 2021. The role of glycometabolic plasticity in cancer. Pathol Res Pract, 226:153595.

[35]PoppMWL, MaquatLE, 2013. Organizing principles of mammalian nonsense-mediated mRNA decay. Annu Rev Genet, 47:139-165.

[36]SneeggenM, GuadagnoNA, ProgidaC, 2020. Intracellular transport in cancer metabolic reprogramming. Front Cell Dev Biol, 8:597608.

[37]SungH, FerlayJ, SiegelRL, et al., 2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 71(3):209-249.

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