Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2024

Open Access 01-12-2024 | Gastric Cancer | Research

YY1: a key regulator inhibits gastric cancer ferroptosis and mediating apatinib-resistance

Authors: Zi-Han Geng, Jun-Xian Du, Yue-Da Chen, Pei-Yao Fu, Ping-Hong Zhou, Wen-Zheng Qin, Yi-Hong Luo

Published in: Cancer Cell International | Issue 1/2024

Login to get access

Abstract

Objective

Gastric cancer (GC) stands as a prevalent and deadly global malignancy. Despite its role as a preoperative neoadjuvant therapy, Apatinib’s effectiveness is curtailed among GC patients exhibiting elevated YY1 expression. YY1’s connection to adverse prognosis, drug resistance, and GC metastasis is established, yet the precise underlying mechanisms remain elusive. This study aims to unravel potential pathogenic pathways attributed to YY1.

Design

Utilizing bioinformatics analysis, we conducted differentially expressed genes, functional annotation, and pathway enrichment analyses, and further validation through cellular and animal experiments.

Results

Higher YY1 expression correlated with diminished postoperative progression-free survival (PFS) and disease-specific survival (DSS) rates in TCGA analysis, identifying YY1 as an independent DSS indicator in gastric cancer (GC) patients. Notably, YY1 exhibited significantly elevated expression in tumor tissues compared to adjacent normal tissues. Bioinformatics analysis revealed noteworthy differentially expressed genes (DEGs), transcriptional targets, factors, and co-expressed genes associated with YY1. LASSO Cox analysis unveiled Transferrin as a prospective pivotal protein regulated by YY1, with heightened expression linked to adverse DSS and PFS outcomes. YY1’s role in governing the p53 signaling pathway and ferroptosis in GC cells was further elucidated. Moreover, YY1 overexpression dampened immune cell infiltration within GC tumors. Additionally, YY1 overexpression hindered GC cell ferroptosis and mediated Apatinib resistance via the p53 pathway. Remarkably, IFN-a demonstrated efficacy in reversing Apatinib resistance and immune suppression in GC tissues.

Conclusions

Our findings underscore the pivotal role of YY1 in driving GC progression and influencing prognosis, thus pinpointing it as a promising therapeutic target to enhance patient outcomes.
Appendix
Available only for authorised users
Literature
1.
Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin, 2021.
2.
Sano T, Coit D G, Kim H H, et al. Proposal of a new stage grouping of gastric cancer for TNM classification: International Gastric Cancer Association staging project [J]. Gastric Cancer. 2017;20(2):217–25.
3.
Japanese gastric cancer treatment guidelines 2018 (5th edition) [J]. Gastric Cancer., 2021, 24(1): 1–21.
4.
Li J, Qin S, Xu J, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial [J]. J Clin Oncol. 2013;31(26):3219–25.CrossRefPubMed
5.
Cheng H, Zong L, Kong Y, et al. Camrelizumab plus Apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial [J]. Lancet Oncol. 2021;22(11):1609–17.CrossRefPubMed
6.
Wang Q, Gao J. Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models [J]. Cancer Immunol Immunother. 2020;69(9):1781–99.CrossRefPubMed
7.
Zhao S, Ren S, Jiang T, et al. Low-dose apatinib optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 blockade in Lung Cancer [J]. Cancer Immunol Res. 2019;7(4):630–43.CrossRefPubMed
8.
Li J, Qin S, Xu J, et al. Randomized, Double-Blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory Advanced or metastatic adenocarcinoma of the stomach or Gastroesophageal Junction [J]. J Clin Oncol. 2016;34(13):1448–54.CrossRefPubMed
9.
Khachigian L M. The Yin and Yang of YY1 in tumor growth and suppression [J]. Int J Cancer. 2018;143(3):460–5.CrossRefPubMed
10.
Meliala I T S, Hosea R, Kasim V, et al. The biological implications of Yin Yang 1 in the hallmarks of cancer [J]. Theranostics. 2020;10(9):4183–200.CrossRefPubMed
11.
Frankish A, Diekhans M, Jungreis I, et al. Gencode 2021 [J]. Nucleic Acids Res. 2021;49(D1):D916–d23.CrossRefPubMed
12.
Ritchie M E, Phipson B. Limma powers differential expression analyses for RNA-sequencing and microarray studies [J]. Nucleic Acids Res. 2015;43(7):e47.CrossRefPubMed
13.
Han H, Cho J W, Lee S, et al. Trrust v2: an expanded reference database of human and mouse transcriptional regulatory interactions [J]. Nucleic Acids Res. 2018;46(D1):D380–d6.CrossRefPubMed
14.
Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data [J]. Nat Commun. 2013;4:2612.CrossRefPubMed
15.
16.
17.
18.
Gao Q, Wang Z C, Duan M et al. Cell Culture System for Analysis of Genetic Heterogeneity within Hepatocellular Carcinomas and Response to Pharmacologic agents [J]. Gastroenterology, 2017, 152(1): 232 – 42.e4.
19.
Du J X, Luo Y H, Zhang SJ, et al. Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1 [J]. J Exp Clin Cancer Res. 2021;40(1):171.CrossRef
20.
Hu B. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma [J]. Biochem Biophys Res Commun. 2015;468(4):525–32.CrossRefPubMed
21.
Fu PY, Hu B, Ma X L, et al. Far upstream element-binding protein 1 facilitates hepatocellular carcinoma invasion and metastasis [J]. Carcinogenesis. 2020;41(7):950–60.
22.
Li H, Li X, Liu S et al. PD-1 checkpoint blockade in combination with an mTOR inhibitor restrains Hepatocellular Carcinoma Growth Induced by Hepatoma Cell-intrinsic PD-1 [J]. Hepatology (Baltimore, Md), 2017.
23.
Kondou H, Mushiake S, Etani Y, et al. A blocking peptide for transforming growth factor-beta1 activation prevents hepatic fibrosis in vivo [J]. J Hepatol. 2003;39(5):742–8.CrossRefPubMed
24.
Kuroki H, Hayashi H, Nakagawa S, et al. Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor beta signal activation and liver regeneration after hepatectomy in an experimental model [J]. Br J Surg. 2015;102(7):813–25.CrossRefPubMed
25.
Hu B, Yu M, Ma X et al. Interferon-a potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment [J]. Cancer Discov, 2022.
26.
Ye Q H, Zhu W W, Zhang JB, et al. GOLM1 modulates EGFR/RTK cell-surface recycling to Drive Hepatocellular Carcinoma metastasis [J]. Cancer Cell. 2016;30(3):444–58.CrossRefPubMed
27.
28.
Sui X, Zhang R, Liu S, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in Colorectal Cancer [J]. Front Pharmacol. 2018;9:1371.CrossRefPubMedPubMedCentral
29.
Hong X. The Lipogenic Regulator SREBP2 induces transferrin in circulating Melanoma cells and suppresses ferroptosis [J]. Cancer Discov. 2021;11(3):678–95.CrossRefPubMed
30.
Tang L J, Zhou Y J, Xiong X M, et al. Ubiquitin-specific protease 7 promotes ferroptosis via activation of the p53/TfR1 pathway in the rat hearts after ischemia/reperfusion [J]. Free Radic Biol Med. 2021;162:339–52.
31.
32.
Donohoe Me, Zhang X. Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality [J]. Mol Cell Biol. 1999;19(10):7237–44.CrossRefPubMedPubMedCentral
33.
34.
Kaufhold S, Garbán H. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication [J]. J Exp Clin Cancer Res. 2016;35:84.CrossRefPubMedPubMedCentral
35.
Bhaskar Rao D, Panneerpandian P, Balakrishnan K, et al. YY1 regulated transcription-based stratification of gastric tumors and identification of potential therapeutic candidates [J]. J Cell Commun Signal. 2021;15(2):251–67.CrossRefPubMed
36.
Panneerpandian P, Devanandan H J Marimuthua, et al. Abacavir induces the transcriptional activity of YY1 and other oncogenic transcription factors in gastric cancer cells [J]. Antiviral Res. 2020;174:104695.CrossRefPubMed
37.
Panneerpandian P, Rao D B Ganesank. Calcium channel blockers lercanidipine and amlodipine inhibit YY1/ERK/TGF-β mediated transcription and sensitize the gastric cancer cells to doxorubicin [J]. Toxicol Vitro. 2021;74:105152.CrossRef
38.
Son H J, Choi E J, Yoo N J, et al. Somatic mutations and Intratumoral Heterogeneity of Cancer-related genes NLK, YY1 and PA2G4 in gastric and colorectal cancers [J]. Pathol Oncol Res. 2020;26(4):2813–5.
39.
Wang J, Wu X. The CCDC43-ADRM1 axis regulated by YY1, promotes proliferation and metastasis of gastric cancer [J]. Cancer Lett. 2020;482:90–101.CrossRefPubMed
40.
Zhang L, Zou L. Relationship between miR-378c and YY1 expression in patients with gastric cancer and the clinicopathological features [J]. Cell Mol Biol Lett. 2021;26(1):12.CrossRefPubMedPubMedCentral
41.
Hays E, Bonavida B. YY1 regulates cancer cell immune resistance by modulating PD-L1 expression [J]. Drug Resist Updat, 2019, 43: 10–28.
42.
Zhou X, Zou L, Liao H, et al. Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8(+) T cell-mediated ferroptosis in castration-resistant prostate cancer [J]. Acta Pharm Sin B. 2022;12(2):692–707.CrossRefPubMed
43.
Yang W S, Sriramaratnam R, Welsch M E et al. Regulation of ferroptotic cancer cell death by GPX4 [J]. Cell, 2014, 156(1–2): 317 – 31.
44.
45.
Zhao L, Peng Y, He S, et al. Apatinib induced ferroptosis by lipid peroxidation in gastric cancer [J]. Gastric Cancer. 2021;24(3):642–54.CrossRefPubMed
46.
Xia L, Gong M, Zou Y et al. Apatinib Induces Ferroptosis of Glioma Cells through Modulation of the VEGFR2/Nrf2 Pathway [J]. Oxid Med Cell Longev, 2022, 2022: 9925919.
47.
48.
Hu B, Yu M, Ma X, et al. IFNα potentiates Anti-PD-1 efficacy by remodeling glucose metabolism in the Hepatocellular Carcinoma Microenvironment [J]. Cancer Discov. 2022;12(7):1718–41.CrossRefPubMed
49.
Willemsen M, Krebbers G, Tjin E P M, et al. IFN-γ-induced PD-L1 expression on human melanocytes is impaired in vitiligo [J]. Exp Dermatol. 2022;31(4):556–66.
Metadata
Title
YY1: a key regulator inhibits gastric cancer ferroptosis and mediating apatinib-resistance
Authors
Zi-Han Geng
Jun-Xian Du
Yue-Da Chen
Pei-Yao Fu
Ping-Hong Zhou
Wen-Zheng Qin
Yi-Hong Luo
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-024-03262-z

Other articles of this Issue 1/2024

Cancer Cell International 1/2024 Go to the issue

Research

Uncovering the cellular and omics characteristics of natural killer cells in the bone marrow microenvironment of patients with acute myeloid leukemia

Research

Identification of SUMOylation-related biomarkers in papillary thyroid carcinoma

Research

METTL14 enhances the m6A modification level of lncRNA MSTRG.292666.16 to promote the progression of non-small cell lung cancer

Research

Exosomes biogenesis was increased in metformin-treated human ovary cancer cells; possibly to mediate resistance

Review

Immune modulation in malignant pleural effusion: from microenvironment to therapeutic implications

Research

Erianin inhibits the progression of triple-negative breast cancer by suppressing SRC-mediated cholesterol metabolism
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
Image Credits