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LncRNA GIMA promotes hepatocarcinoma cell survival via inhibiting ATF4 under metabolic stress

  • School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027,China

Cite this:
https://doi.org/10.52396/JUST-2021-0041
  • Received Date: 03 February 2021
  • Rev Recd Date: 25 February 2021
  • Publish Date: 28 February 2021
    Abstract

  • Abstract

    Tumor cells are usually under nutrient-deficient microenvironment, a series of adaptive responses are adopted to maintain the cell survival and growth under the metabolic stress. However, the regulatory role of long non-coding RNA (lncRNA) in this process still remains elusive.To explore whether lncRNAs involve in regulating the hepatocarcinoma cell survival under the metabolic stress, GIMA(glucose-deprivation induced modulator of ATF4) was identified as an lncRNA induced by glucose deprivation via the transcriptome sequencing, and the upregulation of GIMA depends on the ATF4 activation under glucose deprivation. The Luciferase assay and the chromatin immunoprecipitation assay proved that GIMA is the transcriptional target gene of ATF4. Furthermore, GIMA promotes the hepatocarcinoma cell survival under glucose deprivation via specifically inhibiting ATF4. Taken together,these results suggest that GIMA may be a new potential target for the hepatocarcinoma treatment.

    Abstract

    Tumor cells are usually under nutrient-deficient microenvironment, a series of adaptive responses are adopted to maintain the cell survival and growth under the metabolic stress. However, the regulatory role of long non-coding RNA (lncRNA) in this process still remains elusive.To explore whether lncRNAs involve in regulating the hepatocarcinoma cell survival under the metabolic stress, GIMA(glucose-deprivation induced modulator of ATF4) was identified as an lncRNA induced by glucose deprivation via the transcriptome sequencing, and the upregulation of GIMA depends on the ATF4 activation under glucose deprivation. The Luciferase assay and the chromatin immunoprecipitation assay proved that GIMA is the transcriptional target gene of ATF4. Furthermore, GIMA promotes the hepatocarcinoma cell survival under glucose deprivation via specifically inhibiting ATF4. Taken together,these results suggest that GIMA may be a new potential target for the hepatocarcinoma treatment.
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    • References(35)
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    [1]
    Tameemi W A, Dale T P, Jumaily R M K A, et al.Hypoxia-modified cancer cell metabolism.Front. Cell Dev. Biol., 2019, 7:4.
    [2]
    Pavlova N N, Thompson C B.The emerging hallmarks of cancer metabolism. Cell Metab., 2016, 23(1):27-47.
    [3]
    Liberti M V, Locasale J W.The Warburg Effect: How does it benefit cancer cells?. Trends Biochem. Sci., 2016,41(3):211-218.
    [4]
    Birsoy K, Possemato R, Lorbeer F K, et al.Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature, 2014,508(7494):108-112.
    [5]
    Zeng P, Sun S N, Li R, et al. HER2 upregulates ATF4 to promote cell migration via activation of ZEB1 and downregulation of E-cadherin. Int. J. Mol. Sci., 2019,20(9):2223
    [6]
    Zong Y, Feng S J, Cheng J W, et al.Up-regulated ATF4 expression increases cell sensitivity to apoptosis in response to radiation. Cell. Physiol. Biochem., 2017,41(2):784-794.
    [7]
    Gwinn D M, Lee A G,Campo M B M D, et al.Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell, 2018,33(1):91-107.e6.
    [8]
    Rozpedek W, Pytel D, Mucha B, et al. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med., 2016,16(6):533-544.
    [9]
    Tang Q,Ren L W, Liu J Y, et al. Withaferin a triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4-ATF3-CHOP axis. Cell Prolif., 2020,53(1):e12706.
    [10]
    Liu H C, Chao X, Liu J W, et al.Aspirin exerts anti-tumor effect through inhibiting Blimp1 and activating ATF4/CHOP pathway in multiple myeloma. Biomed. Pharmacother., 2020,125:110005.
    [11]
    Iurlaro R, Püschel F, Annicchiarico C L L,et al. Glucose deprivation induces ATF4-mediated apoptosis through TRAIL death receptors. Mol. Cell. Biol., 2017,37(10): e00479-16.
    [12]
    Dayton T L, Jacks T, Heiden M G V.PKM2, cancer metabolism, and the road ahead. EMBO Rep., 2016,17(12):1721-1730.
    [13]
    Taguchi K, Yamamoto M.The KEAP1-NRF2 system in cancer. Front Oncol., 2017,7:85.
    [14]
    Qian X Y, Zhao J Y, Yeung P Y, et al.Revealing lncRNA structures and interactions by sequencing-based approaches. Trends Biochem. Sci., 2019,44(1):33-52.
    [15]
    Jathar S,Kumar V, Srivastava J,et al. Technological developments in lncRNA biology. Adv. Exp. Med. Biol., 2017,1008:283-323.
    [16]
    Liu Y,Yang Y L,Li L, et al. LncRNA SNHG1 enhances cell proliferation, migration, and invasion in cervical cancer. Biochem. Cell Biol.,2018,96(1):38-43.
    [17]
    Liu C Y, Zhang Y H, Li R B, et al. LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat. Commun., 2018,9(1):29.
    [18]
    Chen L, Yang W J, Guo Y J, et al. Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One, 2017, 12(9):e0185406.
    [19]
    Kern C, Wang Y, Chitwood J, et al.Genome-wide identification of tissue-specific long non-coding RNA in three farm animal species. BMC Genomics, 2018,19(1):684.
    [20]
    Zhu J,Kong F Y, Xing L, et al. Prognostic and clinicopathological value of long noncoding RNA XIST in cance. Clin. Chim. Acta, 2018,479:43-47.
    [21]
    Dang Y, Lan F H, Ouyang X J,et al. Expression and clinical significance of long non-coding RNA HNF1A-AS1 in human gastric cancer. World J. Surg. Oncol., 2015,13:302.
    [22]
    Lu D P, Luo P, Wang Q, et al. lncRNA PVT1 in cancer: A review and meta-analysis. Clin Chim Acta, 2017, 474:1-7.
    [23]
    Han P, Li J W, Zhang B M, et al. The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signaling. Mol. Cancer, 2017, 16(1):9.
    [24]
    Ma T T,Zhou L Q, Xia J H, et al.LncRNA PCAT-1 regulates the proliferation, metastasis and invasion of cervical cancer cells. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(7):1907-1913.
    [25]
    Hartke J,Johnson M, Ghabril M.The diagnosis and treatment of hepatocellular carcinoma. Semin. Diagn. Pathol., 2017, 34(2):153-159.
    [26]
    Ko K L, Mak L Y, Cheung K S,et al. Hepatocellular carcinoma: Recent advances and emerging medical therapies. F1000Res., 2020, 9:F1000 Faculty Rev-620.
    [27]
    Craig A J, Felden J V, Lezana T G, et al.Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol., 2020, 17(3):139-152.
    [28]
    Adams C M, Ebert S M, Dyle M C.Role of ATF4 in skeletal muscle atrophy. Curr. Opin. Clin. Nutr. Metab. Care, 2017, 20(3):164-168.
    [29]
    Bader J E, Voss K, Rathmell J C.Targeting metabolism to improve the tumor microenvironment for cancer immunotherapy. Mol. Cell, 2020, 78(6):1019-1033.
    [30]
    Li X X, Wang Z J,Zheng Y, et al.Nuclear receptor Nur77 facilitates melanoma cell survival under metabolic stress by protecting fatty acid oxidation. Mol. Cell, 2018, 69(3):480-492.e7.
    [31]
    Ye J B, Kumanova M,Hart L S, et al.The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J., 2010, 29(12):2082-2096.
    [32]
    Dey S,Sayers C M, Verginadis I I, et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J. Clin. Invest., 2015, 125(7):2592-2608.
    [33]
    Han J, Back S H, Hur J, et al.ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol., 2013, 15(5):481-490.
    [34]
    Xiao Z D, Han L, Lee H, et al.Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nat. Commun., 2017, 8(1):783.
    [35]
    Liu X W, Xia Z D,Han L, et al.LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat. Cell Biol., 2016, 18(4):431-442.
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