Similar articles

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

[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.