Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (3): 1-12.doi: 10.6040/j.issn.1671-7554.0.2021.1036

   

Regulatory role of histone deacetylase SIRT1 in pancreatic cancer metabolism

YUAN Baowen1, WANG Pei2,3, HUANG Wei1,2   

  1. 1. Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;
    2. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Capital Medical University, Beijing 100069, China;
    3. National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
  • Published:2022-03-09

PDF (PC)

128

Abstract: Objective To explore the regulatory role and mechanism of silent mating-type information regulation 2 homolog 1(SIRT1)in pancreatic cancer metabolism with metabolomic and transcriptomic techniques. Methods RNA-seq data of pancreatic cancer and normal pancreas tissues from TCGA, GTEx, and HPA were analyzed to identify the expression of SIRT1. A total of 6 pairs of SIRT1 knockdown and control groups of pancreatic cancer PANC-1 cell lines were constructed. The metabolite profiles and gene expression profiles were measured using ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)and high-throughput RNA-seq, respectively. Metabolic pathways with significantly different metabolites involved were enriched. The relationship between SIRT1 gene expression and drug responsiveness and drug resistance was analyzed. Results Analysis of TCGA and GTEx data revealed that SIRT1 expression was significantly higher in pancreatic cancer than in normal pancreas tissues; immunohistochemical data from the HPA database further confirmed the higher expression of SIRT1 at the protein level. Untargeted metabolomics and high-throughput RNA-seq identified 59 statistically significantly different metabolites and 688 differentially expressed genes. The differential metabolites were mainly enriched in metabolic pathways such as choline metabolism in cancer, pyrimidine metabolism, and ABC transporters. Fourteen differentially expressed genes were involved in SIRT1-regulated metabolic pathways. These genes were mainly enriched in purine metabolic signaling pathways and involved in biological processes such as ATP binding and small molecule metabolism. CARE online tool showed that higher expression of SIRT1 led to higher responsiveness to many antitumor drugs and resistance to some antitumor drugs. Conclusion Our study reveals that SIRT1 has a regulatory role in pancreatic cancer metabolism, which paves the way for future study on the regulatory mechanism of SIRT1 and targeted therapy for pancreatic cancer.

Key words: Silent mating-type information regulation 2 homolog 1, Pancreatic cancer, Metabolomics, Transcriptomics, Regulatory mechanism

CLC Number: 

  • R735.9
[1] Martinez-Reyes I, Chandel NS. Cancer metabolism: looking forward [J]. Nat Rev Cancer, 2021, 21(10): 669-680.
[2] Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? [J]. Nat Rev Cancer, 2016, 16(10): 635-649.
[3] Xu D, Wang Z, Xia Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis [J]. Nature, 2020, 580(7804): 530-535.
[4] Johansson HJ, Socciarelli F, Vacanti NM, et al. Breast cancer quantitative proteome and proteogenomic landscape [J]. Nat Commun, 2019, 10(1): 1600.
[5] Pascual G, Avgustinova A, Mejetta S, et al.Targeting metastasis-initiating cells through the fatty acid receptor CD36 [J]. Nature, 2017, 541(7635): 41-45.
[6] Aird KM,Zhang R. Nucleotide metabolism, oncogene-induced senescence and cancer[J]. Cancer Lett, 2015, 356(2 Pt A): 204-210.
[7] Release Notice-Canadian Cancer Statistics: a 2020 special report on lung cancer [J]. Health Promot Chronic Dis Prev Can, 2020, 40(9): 325.
[8] 张晓璐, 王丽莉, 陈凯明, 等. 组蛋白去乙酰化酶SIRT1经Toll样受体4途径对巨噬细胞凋亡的调控[J]. 山东大学学报(医学版), 2020, 58(12): 8-14. ZHANG Xiaolu, WANG Lili, CHEN Kaiming, et al. Mechanism of histone deacetylase SIRT1 inhibiting macrophages apoptosis via TLR4 signaling pathway [J]. Journal of Shandong University(Health Sciences), 2020, 58(12): 8-14.
[9] Mei Z, Zhang X, Yi J, et al. Sirtuins in metabolism, DNA repair and cancer [J]. J Exp Clin Cancer Res, 2016, 35(1): 182.
[10] Chalkiadaki A,Guarente L. The multifaceted functions of sirtuins in cancer [J]. Nat Rev Cancer, 2015, 15(10): 608-624.
[11] Knight JR, Milner J. SIRT1, metabolism and cancer [J]. Curr Opin Oncol, 2012, 24(1): 68-75.
[12] Yarahmadi S, Abdolvahabi Z, Hesari Z, et al. Inhibition of sirtuin 1 deacetylase by miR-211-5p provides a mechanism for the induction of cell death in breast cancer cells [J]. Gene, 2019, 711: 143939. doi: 10.1016/j.gene.2019.06.029.
[13] Ji K, Sun X, Liu Y, et al. Regulation of apoptosis and radiation sensitization in lung cancer cells via the Sirt1/NF-kappaB/Smac pathway [J]. Cell Physiol Biochem, 2018, 48(1): 304-316.
[14] 郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2019, 41(1): 19-28. ZHENG Rongshou, SUN Kexin, ZHANG Siwei, et al. Report of cancer epidemiology in China, 2015 [J]. Chinese Journal of Oncology, 2019,41(1): 19-28.
[15] Jin J, Chu Z, Ma P, et al. SIRT1 promotes the proliferation and metastasis of human pancreatic cancer cells [J]. Tumour Biol, 2017, 39(3): 1010428317691180.
[16] Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism [J]. Nat Rev Cancer, 2011, 11(2): 85-95.
[17] Mcdonald OG, Li X, Saunders T, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis [J]. Nat Genet, 2017, 49(3): 367-376.
[18] Chang CH, Qiu J, Osullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer Progression [J]. Cell, 2015, 162(6): 1229-1241.
[19] Qin C, Yang G, Yang J, et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies [J]. Mol Cancer, 2020, 19(1): 50.
[20] Chini CC, Espindola-Netto JM, Mondal G, et al. SIRT1-activating compounds(STAC)negatively regulate pancreatic cancer cell growth and viability through a SIRT1 lysosomal-dependent pathway [J]. Clin Cancer Res, 2016, 22(10): 2496-2507.
[21] Chiarugi A, Dolle C, Felici R, et al. The NAD metabolome - a key determinant of cancer cell biology [J]. Nat Rev Cancer, 2012, 12(11): 741-752.
[22] Ju HQ, Zhuang ZN, Li H, et al. Regulation of the nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer [J]. Cancer Lett, 2016, 379(1): 1-11.
[23] Chini CC, Guerrico AM, Nin V, et al. Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors [J]. Clin Cancer Res, 2014, 20(1): 120-130.
[24] Cortellini A, Cannita K, Parisi A, et al. Timedflat infusion of 5fluorouracil with docetaxel and oxaliplatin as firstline treatment of gastroesophageal adenocarcinoma: a single institution experience with the FD/FOx regimen [J]. Oncol Rep, 2018, 40(2): 803-812.
[25] Chen W, Zhan P, Wu J, et al. The development of HEPT-type HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family [J]. Curr Pharm Des, 2012, 18(27): 4165-4186.
[26] Balasubramaniyan V, Bhat K. Targeting pyrimidine metabolism for glioblastoma therapy [J]. Neuro Oncol, 2020, 22(2): 169-170.
[27] Shukla SK, Purohit V, Mehla K, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer [J]. Cancer Cell, 2017, 32(3): 71-87.
[28] Santana-Codina N, Roeth AA, Zhang Y, et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis [J]. Nat Commun, 2018, 9(1): 4945.
[29] Morita M, Imanaka T. Peroxisomal ABC transporters: structure, function and role in disease [J]. Biochim Biophys Acta, 2012, 1822(9): 1387-1396.
[30] Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters [J]. Nat Rev Cancer, 2002, 2(1): 48-58.
[31] Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: what is the way forward? [J]. World J Gastroenterol, 2018, 24(29): 3222-3238.
[32] Mottini C, Tomihara H, Carrella D, et al. Predictive signatures inform the effective repurposing of decitabine to treat KRAS-dependent pancreatic ductal adenocarcinoma[J]. Cancer Res, 2019, 79(21): 5612-5625.
[1] ZHANG Gaorui, ZHANG Yuting, ZHAO Yuxuan, WANG Fangqing, YU Dexin. Value of MnFe2O4@CNS in the theragnostic of pancreatic cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(4): 48-55.
[2] XU Yujun, LIU Ming, HE Xiangmeng, LI Chengli. 1.0T open MRI-guided 125I seeds percutaneous implantation for advanced pancreatic cancer [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(2): 21-25.
[3] YU Fei, LIU Shaozhuang, ZHONG Mingwei, HUANG Xin, JIAO Jie, HU Sanyuan, YU Wenbin. Metabolomics analysis of colorectal cancer based on GC-TOF-MS [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(7): 60-68.
[4] SUN Xuyi, HAN Jiankui. Dual-Phase 18F-FDG PET/CT in the diagnosis of benign and malignant pancreatic lesions [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(4): 68-73.
[5] LIU Yingjun, ZHANG Tao, WANG Lu, LIU Jia, CHANG Xuerun, ZHANG Jingxuan, XUE Fuzhong. Serum metabolic profiling of schizophrenia based on random forest [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(2): 92-96.
[6] LI Hongxia, DONG Lei, JIANG Jiong, WANG Xinyang. Effects of peptide YY on apoptosis of human pancreatic cancer cell line Miapaca-2 in vitro [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(12): 7-11.
[7] LI Mei-ying1, LI Ji-sheng1, YU Xue-jun1, SUN Li-mei1, WANG Ai-jun1, LIU Qi-ji2, WANG Xiu-wen1. Effects of bufalin on the proliferation and cell cycle of human pancreatic cancer CAPAN-2 cells [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2013, 51(11): 37-41.
[8] ZHENG Hong-min. Expression of molealar imaging marker folate receptor alpha in pancreatic cancer and its significance [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2010, 48(3): 83-85.
[9]

CUI Yazhou1, JIA Qing2, WANG Zhaopeng2, WANG Zhaoxia2,
ZHANG Yueying2, ZHANG Weidong2, HAN Jinxiang1

.

Polypeptide extract from scorpion venom inhibits
liver metastasis in pancreatic cancer

[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2009, 47(03): 20-22.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd