Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2021 | Research

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

Authors: Hui-er Zhu, Tao Li, Shengnan Shi, De-xiong Chen, Weiping Chen, Hui Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown.

Methods

Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD.

Results

We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation.

Conclusions

Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

Available only for authorised users

Lambe G, Durand M, Buckley A, Nicholson S, McDermott R. Adenocarcinoma of the lung: from BAC to the future. Insights Imaging. 2020;11(1):69.PubMedPubMedCentralCrossRef

Liang W, Zhang L, Jiang G, Wang Q, Liu L, Liu D, et al. Development and validation of a nomogram for predicting survival in patients with resected non-small-cell lung cancer. J Clin Oncol. 2015;33(8):861–9.PubMedCrossRef

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.PubMedCrossRef

Zhu HE, Yin JY, Chen DX, He S, Chen H. Agmatinase promotes the lung adenocarcinoma tumorigenesis by activating the NO-MAPKs-PI3K/Akt pathway. Cell Death Dis. 2019;10(11):854.PubMedPubMedCentralCrossRef

Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA, et al. ALK resistance mutations and efficacy of Lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung Cancer. J Clin Oncol. 2019;37(16):1370–9.PubMedPubMedCentralCrossRef

Kobayashi K, Soejima K, Fukunaga K, Shintani Y, Sekine I, Shukuya T, et al. Key prognostic factors for EGFR-mutated non-adenocarcinoma lung cancer patients in the Japanese joint Committee of Lung Cancer Registry Database. Lung Cancer. 2020;146:236–43.PubMedCrossRef

Chen JA, Riess JW. Optimal Management of Patients with advanced NSCLC harboring high PD-L1 expression and driver mutations. Curr Treat Options in Oncol. 2020;21(7):60.CrossRef

Sankar K, Gadgeel SM, Qin A. Molecular therapeutic targets in non-small cell lung cancer. Expert Rev Anticancer Ther. 2020;20(8):647–61.PubMedCrossRef

Noor ZS, Cummings AL, Johnson MM, Spiegel ML, Goldman JW. Targeted therapy for non-small cell lung Cancer. Semin Respir Crit Care Med. 2020;41(3):409–34.PubMedCrossRef

10.

Gu J, Yao W, Shi P, Zhang G, Owonikoko TK, Ramalingam SS, et al. MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers. Cancer. 2020;126(16):3788–99.PubMedCrossRef

11.

Calvayrac O, Pradines A, Pons E, Mazieres J, Guibert N. Molecular biomarkers for lung adenocarcinoma. Eur Respir J. 2017;49(4):1601734.PubMedCrossRef

12.

Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel). 2018;10(8):248.CrossRef

13.

Alomer RM, da Silva EML, Chen J, Piekarz KM, McDonald K, Sansam CG, et al. Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression. Proc Natl Acad Sci U S A. 2017;114(37):9906–11.PubMedPubMedCentralCrossRef

14.

Guo XB, Huang B, Pan YH, Su SG, Li Y. ESCO2 inhibits tumor metastasis via transcriptionally repressing MMP2 in colorectal cancer. Cancer Manag Res. 2018;10:6157–66.PubMedPubMedCentralCrossRef

15.

Wang QL, Liu L. Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma. J Clin Lab Anal. 2020;34(5):e23163.PubMedPubMedCentralCrossRef

16.

Xiao B, Chen L, Ke Y, Hang J, Cao L, Zhang R, et al. Identification of methylation sites and signature genes with prognostic value for luminal breast cancer. BMC Cancer. 2018;18(1):405.PubMedPubMedCentralCrossRef

17.

Zhang W, Cui Q, Qu W, Ding X, Jiang D, Liu H. TRIM58/cg26157385 methylation is associated with eight prognostic genes in lung squamous cell carcinoma. Oncol Rep. 2018;40(1):206–16.PubMedPubMedCentral

18.

Ryu B, Kim DS, Deluca AM, Alani RM. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One. 2007;2(7):e594.PubMedPubMedCentralCrossRef

19.

Chen H, Zhang L, He W, Liu T, Zhao Y, Chen H, et al. ESCO2 knockdown inhibits cell proliferation and induces apoptosis in human gastric cancer cells. Biochem Biophys Res Commun. 2018;496(2):475–81.PubMedCrossRef

20.

Kedzierska H, Piekielko-Witkowska A. Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer. Cancer Lett. 2017;396:53–65.PubMedCrossRef

21.

Kutluay SB, Emery A, Penumutchu SR, Townsend D, Tenneti K, Madison MK, et al. Genome-Wide Analysis of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) Binding to HIV-1 RNA Reveals a Key Role for hnRNP H1 in Alternative Viral mRNA Splicing. J Virol. 2019;93(21):e01048–19.PubMedPubMedCentralCrossRef

22.

Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab. 2012;23(11):560–6.PubMedPubMedCentralCrossRef

23.

David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463(7279):364–8.PubMedCrossRef

24.

Kuranaga Y, Sugito N, Shinohara H, Tsujino T, Taniguchi K, Komura K, et al. SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells. Int J Mol Sci. 2018;19(10):3012.PubMedCentralCrossRef

25.

Robbins Y, Greene S, Friedman J, Clavijo PE, Van Waes C, Fabian KP, et al. Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells. Elife. 2020;9:e54854.PubMedPubMedCentralCrossRef

26.

Huang JZ, Chen M, Chen D, Gao XC, Zhu S, Huang H, et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses Colon Cancer growth. Mol Cell. 2017;68(1):171–84 e6.PubMedCrossRef

27.

Chabot B, LeBel C, Hutchison S, Nasim FH, Simard MJ. Heterogeneous nuclear ribonucleoprotein particle a/B proteins and the control of alternative splicing of the mammalian heterogeneous nuclear ribonucleoprotein particle A1 pre-mRNA. Prog Mol Subcell Biol. 2003;31:59–88.PubMedCrossRef

28.

Izaurralde E, Jarmolowski A, Beisel C, Mattaj IW, Dreyfuss G, Fischer U. A role for the M9 transport signal of hnRNP A1 in mRNA nuclear export. J Cell Biol. 1997;137(1):27–35.PubMedPubMedCentralCrossRef

29.

Iijima M, Suzuki M, Tanabe A, Nishimura A, Yamada M. Two motifs essential for nuclear import of the hnRNP A1 nucleocytoplasmic shuttling sequence M9 core. FEBS Lett. 2006;580(5):1365–70.PubMedCrossRef

30.

Chen M, David CJ, Manley JL. Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nat Struct Mol Biol. 2012;19(3):346–54.PubMedPubMedCentralCrossRef

31.

Chen M, Sheng XJ, Qin YY, Zhu S, Wu QX, Jia L, et al. TBC1D8 amplification drives tumorigenesis through metabolism reprogramming in ovarian Cancer. Theranostics. 2019;9(3):676–90.PubMedPubMedCentralCrossRef

32.

Guo R, Li Y, Ning J, Sun D, Lin L, Liu X. HnRNP A1/A2 and SF2/ASF regulate alternative splicing of interferon regulatory factor-3 and affect immunomodulatory functions in human non-small cell lung cancer cells. PLoS One. 2013;8(4):e62729.PubMedPubMedCentralCrossRef

33.

Yang H, Zhu R, Zhao X, Liu L, Zhou Z, Zhao L, et al. Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma. Oncogene. 2019;38(25):4915–31.PubMedCrossRef

34.

Carabet LA, Leblanc E, Lallous N, Morin H, Ghaidi F, Lee J, et al. Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer. Molecules. 2019;24(4):763.PubMedCentralCrossRef

35.

Yu C, Guo J, Liu Y, Jia J, Jia R, Fan M. Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation. J Cell Physiol. 2015;230(9):2252–61.PubMedCrossRef

36.

Taniguchi K, Sugito N, Shinohara H, Kuranaga Y, Inomata Y, Komura K, et al. Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression. Int J Mol Sci. 2018;19(5):1276.PubMedCentralCrossRef

37.

Massari F, Ciccarese C, Santoni M, Iacovelli R, Mazzucchelli R, Piva F, et al. Metabolic phenotype of bladder cancer. Cancer Treat Rev. 2016;45:46–57.PubMedCrossRef

38.

Calabretta S, Bielli P, Passacantilli I, Pilozzi E, Fendrich V, Capurso G, et al. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. Oncogene. 2016;35(16):2031–9.PubMedCrossRef

39.

Zhao X, Zhu Y, Hu J, Jiang L, Li L, Jia S, et al. Shikonin inhibits tumor growth in mice by suppressing pyruvate kinase M2-mediated aerobic glycolysis. Sci Rep. 2018;8(1):14517.PubMedPubMedCentralCrossRef

40.

Liu M, Wang Y, Ruan Y, Bai C, Qiu L, Cui Y, et al. PKM2 promotes reductive glutamine metabolism. Cancer Biol Med. 2018;15(4):389–99.PubMedPubMedCentralCrossRef

41.

Rahman S, Jones MJ, Jallepalli PV. Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells. Proc Natl Acad Sci U S A. 2015;112(36):11270–5.PubMedPubMedCentralCrossRef

42.

Ooi L, Wood IC. Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet. 2007;8(7):544–54.PubMedCrossRef

43.

Qureshi IA, Gokhan S, Mehler MF. REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions. Cell Cycle. 2010;9(22):4477–86.PubMedPubMedCentralCrossRef

Title: ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation
Authors: Hui-er Zhu
Tao Li
Shengnan Shi
De-xiong Chen
Weiping Chen
Hui Chen
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01858-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Neuromedin U induces an invasive phenotype in CRC cells expressing the NMUR2 receptor

TRIM37 orchestrates renal cell carcinoma progression via histone H2A ubiquitination-dependent manner

Hsa_circ_0004296 inhibits metastasis of prostate cancer by interacting with EIF4A3 to prevent nuclear export of ETS1 mRNA

Correction to: Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma

CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization

José Baselga M.D., Ph.D. (1959–2021) leading cancer researcher and oncologist

Keynote webinar | Spotlight on antibody–drug conjugates in cancer