PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

Abstract

	•Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells.
	•The expression of PYCR1 in LC is regulated by DNA methylation.
	•Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells.
	•PYCR1 regulates the transcriptional activity of IRS1 by affecting H3K18 lactylation in its promoter region.

Keywords

h3k18 / irs1 / lactylation / liver cancer / pycr1

References

[1] SungH, FerlayJ, SiegelRL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209-249.

[2] RumgayH, ArnoldM, FerlayJ, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022; 77: 1598-1606.

[3] AnwanwanD, SinghSK, SinghS, Saikam V, SinghV. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 2020; 1873: 188314.

[4] Galicia-MorenoM, Silva-Gomez JA, Lucano-LanderosS, et al. Liver cancer: therapeutic challenges and the importance of experimental models. Can J Gastroenterol Hepatol. 2021; 2021: 8837811.

[5] Martínez-ReyesI, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021; 21: 669-680.

[6] PavlovaNN, ZhuJ, ThompsonCB. The hallmarks of cancer metabolism: still emerging. Cell Metab. 2022: 34(3): 355-377.

[7] LiX, Ramadori P, PfisterD, SeehawerM, ZenderL, HeikenwalderM. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021; 21: 541-557.

[8] TenenDG, ChaiL, TanJL. Metabolic alterations and vulnerabilities in hepatocellular carcinoma. Gastroenterol Rep (Oxf). 2021; 9: 1-13.

[9] SatrianoL, Lewinska M, RodriguesPM, BanalesJM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol. 2019; 16: 748-766.

[10] SunL, SuoC, LiS-t, Zhang H, GaoP. Metabolic reprogramming for cancer cells and their microenvironment: beyond the Warburg effect. Biochim Biophys Acta Rev Cancer. 2018; 1870: 51-66.

[11] SchwartzL, Supuran CT, AlfaroukKO. The Warburg effect and the hallmarks of cancer. Anticancer Agents Med Chem. 2017; 17: 164-170.

[12] AmannT, Hellerbrand C. GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opin Ther Targets. 2009; 13: 1411-1427.

[13] KimYH, JeongDC, PakK, et al. SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget. 2017; 8: 68381.

[14] WuCH, HoYS, TsaiCY, et al. In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer. 2009; 124: 2210-2219.

[15] JiaoL, ZhangH-L, LiD-D, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018; 14: 671-684.

[16] LisP, Dyląg M, NiedźwieckaK, et al. the hk2 dependent “warburg effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules. 2016; 21: 1730.

[17] JanpipatkulK, SuksenK, BorwornpinyoS, et al. Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration. Cell Signal. 2014; 26: 1668-1679.

[18] MichaelAOA, KoS, TaoJ, et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by β-catenin mutations. Cell Metab. 2019; 29: 1135-1150.

[19] StineZE, SchugZT, SalvinoJM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022; 21: 141-162.

[20] GengP, QinW, XuG. Proline metabolism in cancer. Amino Acids. 2021; 53: 1769-1777.

[21] PhangJM. Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxid Redox Signal. 2019; 30: 635-649.

[22] LiY, XuJ, BaoP, et al. Survival and clinicopathological significance of PYCR1 expression in cancer: a meta-analysis. Front Oncol. 2022; 12: 985613.

[23] KayEJ, Paterson K, Riera-DomingoC, et al. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumourigenic extracellular matrix. Nat Metab. 2022; 4: 693-710.

[24] GaoY, LuoL, XieY, ZhaoY, YaoJ, LiuX. PYCR1 knockdown inhibits the proliferation, migration, and invasion by affecting JAK/STAT signaling pathway in lung adenocarcinoma. Mol Carcinog. 2020; 59: 503-511.

[25] SanjanaNE, ShalemO, ZhangF. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014; 11: 783-784.

[26] GalleE, WongC-W, GhoshA, et al. H3K18 lactylation marks tissue-specific active enhancers. Genome Biol. 2022; 23: 207.

[27] ZhangD, TangZ, HuangH, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019; 574: 575-580.

[28] DeBerardinisRJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016; 2: e1600200.

[29] Martinez-OutschoornUE, Peiris-Pagés M, PestellRG, SotgiaF, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017; 14: 11-31.

[30] CuiB, HeB, HuangY, et al. Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress. Cell Death Dis. 2023; 14: 682.

[31] ZhengK, ShaN, HouG, et al. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumour growth under hypoxia. Nat Commun. 2023; 14: 6117.

[32] AhmedM, BiswasT, MondalS. The strategic involvement of IRS in cancer progression. Biochem Biophys Res Commun. 2023; 680: 141-160.

[33] SinghP, AlexJM, BastF. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signalling systems: novel treatment strategies for cancer. Med Oncol. 2014; 31: 805.

[34] AlvesAPNR, Fernandes JC, FenerichBA, et al. IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signalling in acute lymphoblastic leukemia cells. Cancer Lett. 2019; 456: 59-68.

[35] ArkunY. Dynamic modeling and analysis of the cross-talk between insulin/AKT and MAPK/ERK signalling pathways. PLoS One. 2016; 11: e0149684.

[36] BouzakriK, Zachrisson A, Al-KhaliliL, et al. siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metab. 2006; 4: 89-96.

[37] ReissK, Del Valle L, LassakA, TrojanekJ. Nuclear IRS-1 and cancer. J Cell Physiol. 2012; 227: 2992-3000.

[38] GaoC, ZhangH, ZhangW-S, Fang L. Expression and significance of insulin receptor substrate 1 in human hepatocellular carcinoma. Dis Markers. 2020; 2020: 7174062.

[39] SakuraiY, KubotaN, TakamotoI, et al. Role of insulin receptor substrates in the progression of hepatocellular carcinoma. Sci Rep. 2017; 7: 5387.

[40] HamanakaRB, Chandel NS. Cell biology. Warburg effect and redox balance. Science. 2011; 334: 1219-1220.

[41] ChengJ, YehETH. Lactate: an intracellular metabolite regulates cell cycle progression. Life Metab. 2023; 2: load017.

[42] DeWaalD, Nogueira V, TerryAR, et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018; 9: 446.

[43] FengJ, LiJ, WuL, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020; 39: 126.

[44] LiuP, JiH, LiF. MRE11 lactylation: a linker between Warburg effect and DNA repair. Life Metab. 2024; 3: loae013.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.