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On-line Access: 2023-01-10

Received: 2022-04-18

Revision Accepted: 2022-08-19

Crosschecked: 2023-01-16

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Ye Chen


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Journal of Zhejiang University SCIENCE B

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Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways

Author(s):  Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN

Affiliation(s):  Department of Genetics, and Department of Genetic and Metabolic Disease, The Childrens Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; more

Corresponding email(s):  yechency@zju.edu.cn, panrl@zju.edu.cn

Key Words:  Transfer RNA (tRNA); tRNA methyltransferase 5 (TRMT5); Hepatocellular carcinoma (HCC); Hypoxia-inducible factor-1α (HIF-1α)

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Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN. Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways[J]. Journal of Zhejiang University Science B, 2023, 24(4): 50-63.

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author="Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

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%T Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways
%A Qiong ZHAO
%A Luwen ZHANG
%A Qiufen HE
%A Zhiqiang WANG
%A Hongcui CAO
%A Ying ZHOU
%A Ruolang PAN
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 1
%P 50-63
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer

T1 - Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways
A1 - Qiong ZHAO
A1 - Luwen ZHANG
A1 - Qiufen HE
A1 - Hui CHANG
A1 - Zhiqiang WANG
A1 - Hongcui CAO
A1 - Ying ZHOU
A1 - Ruolang PAN
A1 - Ye CHEN
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 1
SP - 50
EP - 63
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.


概要:越来越多研究表明转运RNA(tRNA)修饰与肿瘤进程有关。本研究首次探索了线粒体tRNA G37位甲基化修饰酶TRMT5(tRNA甲基转移酶5)在肝细胞癌发生发展中的作用。生物信息学和临床分析发现TRMT5在肝癌组织中高表达且与预后不良相关。体内外实验表明TRMT5敲低可诱导肝癌细胞代谢重编程,减弱肝癌细胞的增殖和转移能力。进一步研究发现TRMT5敲低降低了肝癌细胞内缺氧诱导因子1α(HIF-1α)的稳定性,进而抑制肝癌细胞生长与转移。此外,TRMT5敲低还导致肝癌细胞对阿霉素的敏感性增加。综上所述,本研究表明靶向TRMT5可以抑制肝癌进程并提升肝癌细胞对化疗药物的敏感性。因此,TRMT5是一个新的致癌候选基因,可以作为肝癌治疗的潜在靶点。


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


[1]AkulaSM, AbramsSL, SteelmanLS, et al., 2019. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets, 23(11):915-929.

[2]ArnasonT, HarknessT, 2015. Development, maintenance, and reversal of multiple drug resistance: at the crossroads of TFPI1, ABC transporters, and HIF1. Cancers (Basel), 7(4):2063-2082.

[3]BarbieriI, KouzaridesT, 2020. Role of RNA modifications in cancer. Nat Rev Cancer, 20(6):303-322.

[4]BergmanPJ, 2019. Cancer immunotherapies. Vet Clin North Am: Small Anim Pract, 49(5):881-902.

[5]BlatchleyMR, HallF, WangSN, et al., 2019. Hypoxia and matrix viscoelasticity sequentially regulate endothelial progenitor cluster-based vasculogenesis. Sci Adv, 5(3):eaau7518.

[6]BowyerC, LewisAL, LloydAW, et al., 2017. Hypoxia as a target for drug combination therapy of liver cancer. Anti-Cancer Drugs, 28(7):771-780.

[7]ChristianT, GamperH, HouYM, 2013. Conservation of structure and mechanism by Trm5 enzymes. RNA, 19(9):1192-1199.

[8]ChunYS, KimMS, ParkJW, 2002. Oxygen-dependent and -independent regulation of HIF-1alpha. J Korean Med Sci, 17(5):581-588.

[9]DimriM, SatyanarayanaA, 2020. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel), 12(2):491.

[10]DoegeK, HeineS, JensenI, et al., 2005. Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intact. Blood, 106(7):2311-2317.

[11]EllinghausP, HeislerI, UnterschemmannK, et al., 2013. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med, 2(5):611-624.

[12]EndresL, FasulloM, RoseR, 2019. tRNA modification and cancer: potential for therapeutic prevention and intervention. Future Med Chem, 11(8):885-900.

[13]FornerA, LlovetJM, BruixJ, 2012. Hepatocellular carcinoma. Lancet, 379(9822):1245-1255.

[14]GiraudJ, ChalopinD, BlancJF, et al., 2021. Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol, 12:655697.

[15]HeQH, YangL, GaoKP, et al., 2020. FTSJ1 regulates tRNA 2'-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression. Cell Death Dis, 11(5):348.

[16]JiJF, WangXW, 2012. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin Oncol, 39(4):461-472.

[17]KeQD, CostaM, 2006. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol, 70(5):1469-1480.

[18]KingGT, SharmaP, DaviesSL, et al., 2018. Immune and autoimmune-related adverse events associated with immune checkpoint inhibitors in cancer therapy. Drugs Today (Barc), 54(2):103-122.

[19]KirchnerS, IgnatovaZ, 2015. Emerging roles of tRNA in adaptive translation, signalling dynamics and disease. Nat Rev Genet, 16(2):98-112.

[20]LiM, SuYD, GaoXY, et al., 2022. Transition of autophagy and apoptosis in fibroblasts depends on dominant expression of HIF-1α or p53. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(3):204-217.

[21]LiuXF, QinSK, 2019. Immune checkpoint inhibitors in hepatocellular carcinoma: opportunities and challenges. Oncologist, 24(S1):S3-S10.

[22]LuoDJ, WangZX, WuJY, et al., 2014. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int, 2014:409272.

[23]MaJ, HanH, HuangY, et al., 2021. METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression. Mol Ther, 29(12):3422-3435.

[24]MasoudGN, LiW, 2015. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B, 5(5):378-389.

[25]McCubreyJA, RakusD, GizakA, et al., 2016. Effects of mutations in Wnt/β‍-catenin, hedgehog, notch and PI3K pathways on GSK-3 activity-diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta (BBA)‍-Mol Cell Res, 1863(12):2942-2976.

[26]Méndez-BlancoC, FondevilaF, Fernández-PalancaP, et al., 2019. Stabilization of hypoxia-inducible factors and BNIP3 promoter methylation contribute to acquired sorafenib resistance in human hepatocarcinoma cells. Cancers (Basel), 11(12):1984.

[27]PowellCA, KopajtichR, D'SouzaAR, et al., 2015. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet, 97(2):319-328.

[28]Prieto-DomínguezN, Méndez-BlancoC, Carbajo-PescadorS, et al., 2017. Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy. Oncotarget, 8(53):91402-91414.

[29]Rosselló‍-TortellaM, Llinàs-AriasP, SakaguchiY, et al., 2020. Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proc Natl Acad Sci USA, 117(34):20785-20793.

[30]SuzukiT, 2021. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol, 22(6):375-392.

[31]SuzukiT, NagaoA, SuzukiT, 2011. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet, 45:299-329.

[32]UrtasunRC, KochCJ, FrankoAJ, et al., 1986. A novel technique for measuring human tissue pO2 at the cellular level. Br J Cancer, 54(3):453-457.

[33]VadlapatlaRK, VadlapudiAD, MitraAK, 2013. Hypoxia-inducible factor-1 (HIF-1): a potential target for intervention in ocular neovascular diseases. Curr Drug Targets, 14(8):919-935.

[34]WardC, LangdonSP, MullenP, et al., 2013. New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev, 39(2):171-179.

[35]WheatonWW, WeinbergSE, HamanakaRB, et al., 2014. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 3:e02242.

[36]WingD, 2020. Characterisation of RNA Modifications in Human Cancer Cells. PhD Dissemination, University of Cambridge, Cambridge, UK.

[37]WuQ, YangZP, NieYZ, et al., 2014. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett, 347(2):159-166.

[38]YamamotoT, FujimuraA, WeiFY, et al., 2019. 2-Methylthio conversion of N6-isopentenyladenosine in mitochondrial trnas by CDK5RAP1 promotes the maintenance of glioma-initiating cells. iScience, 21:42-56.

[39]YanX, QuX, LiuB, et al., 2021. Autophagy-induced HDAC6 activity during hypoxia regulates mitochondrial energy metabolism through the β‍-catenin/COUP-TFII axis in hepatocellular carcinoma cells. Front Oncol, 11:742460.

[40]YangY, ZhangGM, GuoFZ, et al., 2020. Mitochondrial UQCC3 modulates hypoxia adaptation by orchestrating OXPHOS and glycolysis in hepatocellular carcinoma. Cell Rep, 33(5):108340.

[41]YoestJM, 2017. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review. Immunotargets Ther, 6:73-82.

[42]ZhongC, LiYR, YangJ, et al., 2021. Immunotherapy for hepatocellular carcinoma: current limits and prospects. Front Oncol, 11:589680.

[43]ZuoQZ, HeJ, ZhangS, et al., 2021. PPARγ coactivator-1α suppresses metastasis of hepatocellular carcinoma by inhibiting warburg effect by PPARγ-dependent WNT/β‍-catenin/pyruvate dehydrogenase kinase isozyme 1 axis. Hepatology, 73(2):644-660.

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