Effects of Methylation and Transcription Factor YY1 on ID2 Expression in Non-small Cell Lung Carcinoma Cells

Overview

Journal Am J Cancer Res

Specialty Oncology

Date 2024 Jun 11

PMID 38859862

Authors

Yi-Hsin Tseng

Wen-Ru Chou

Wei-Lun Liu

Zhong-Xuan Dung

Ching-Hao Lin

Chia-Hung Hsieh

Chi-Chung Wang

Affiliations

Soon will be listed here.

Abstract

The inhibitor of DNA-binding 2 (ID2) plays a major role in tumor dedifferentiation in non-small cell lung cancer (NSCLC). Studies have indicated an inverse correlation between ID2 expression and NSCLC cell invasiveness. However, the mechanisms through which ID2 activation is regulated are currently unclear. We overexpressed ID2 in H1299 cells and extensively characterized their cellular behaviors. By employing a serial deletion approach combined with a reporter assay, we pinpointed the basal promoter region of . We also examined the DNA methylation status of the promoter to elucidate the epigenetic mechanisms driving ID2 regulation. Our results revealed that ID2 overexpression effectively inhibited the migration, invasion, proliferation, and colony formation abilities of H1299 cells. The region from -243 to +202 played a major role in driving the transcriptional activity of . Sequence analysis results indicated that the transcription factor Yin Yang 1 (YY1) might be crucial in the regulation of ID2 expression. The ectopically expressed YY1 activated both the expression levels of ID2 and the transcriptional activity of the promoter, potentially contributing to its repressive activity on cancer cell growth. Furthermore, site-directed mutagenesis and chromatin immunoprecipitation assays revealed that YY1 may target the -120 and -76 sites of the promoter, thereby activating its transcriptional activity. The promoter regions were also fully methylated in CL1-5 cells, and the methylation level was correlated with the expression levels of the promoter. Moreover, the YY1-induced suppression of colony formation was counteracted by ID2 knockdown, which suggests that YY1 represses cell colony growth through the regulation of ID2. Our results indicate that YY1 plays a role in transactivating ID2 expression and might also contribute to the repression of colony growth through the regulation of ID2.

References

Begon D, Delacroix L, Vernimmen D, Jackers P, Winkler R . Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells. J Biol Chem. 2005; 280(26):24428-34. DOI: 10.1074/jbc.M503790200. View

Perk J, Iavarone A, Benezra R . Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005; 5(8):603-14. DOI: 10.1038/nrc1673. View

Allouche A, Nolens G, Tancredi A, Delacroix L, Mardaga J, Fridman V . The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors. Breast Cancer Res. 2008; 10(1):R9. PMC: 2374961. DOI: 10.1186/bcr1851. View

Sultana A, Alam M, Liu X, Sharma R, Singla R, Gundamaraju R . Single-cell RNA-seq analysis to identify potential biomarkers for diagnosis, and prognosis of non-small cell lung cancer by using comprehensive bioinformatics approaches. Transl Oncol. 2022; 27:101571. PMC: 9676382. DOI: 10.1016/j.tranon.2022.101571. View

Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba M . PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002; 18(2):333-4. DOI: 10.1093/bioinformatics/18.2.333. View

Zhao T, Jia H, Zhang Z, Zhao X, Zou Y, Zhang W . LncRNA H19 regulates ID2 expression through competitive binding to hsa-miR-19a/b in acute myelocytic leukemia. Mol Med Rep. 2017; 16(3):3687-3693. DOI: 10.3892/mmr.2017.7029. View

Wang C, Tsai M, Dai T, Hong T, Chan W, Chen J . Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res. 2007; 67(10):4816-26. DOI: 10.1158/0008-5472.CAN-07-0504. View

Xu S, Wang Y, Li Y, Zhang L, Wang C, Wu X . Comprehensive analysis of inhibitor of differentiation/DNA-binding gene family in lung cancer using bioinformatics methods. Biosci Rep. 2020; 40(2). PMC: 7012656. DOI: 10.1042/BSR20193075. View

Antonangelo L, Tuma T, Fabro A, Acencio M, Terra R, Parra E . Id-1, Id-2, and Id-3 co-expression correlates with prognosis in stage I and II lung adenocarcinoma patients treated with surgery and adjuvant chemotherapy. Exp Biol Med (Maywood). 2016; 241(11):1159-68. PMC: 4950313. DOI: 10.1177/1535370216632623. View

10.

Sarvagalla S, Kolapalli S, Vallabhapurapu S . The Two Sides of YY1 in Cancer: A Friend and a Foe. Front Oncol. 2019; 9:1230. PMC: 6879672. DOI: 10.3389/fonc.2019.01230. View

11.

Rollin J, Blechet C, Regina S, Tenenhaus A, Guyetant S, Gidrol X . The intracellular localization of ID2 expression has a predictive value in non small cell lung cancer. PLoS One. 2009; 4(1):e4158. PMC: 2612745. DOI: 10.1371/journal.pone.0004158. View

12.

Norton J, Deed R, Craggs G, Sablitzky F . Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol. 1998; 8(2):58-65. View

13.

Hasskarl J, Munger K . Id proteins--tumor markers or oncogenes?. Cancer Biol Ther. 2002; 1(2):91-6. DOI: 10.4161/cbt.50. View

14.

Kamalian L, Gosney J, Forootan S, Foster C, Bao Z, Beesley C . Increased expression of Id family proteins in small cell lung cancer and its prognostic significance. Clin Cancer Res. 2008; 14(8):2318-25. DOI: 10.1158/1078-0432.CCR-07-4716. View

15.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

16.

Yokota Y, Mori S . Role of Id family proteins in growth control. J Cell Physiol. 2002; 190(1):21-8. DOI: 10.1002/jcp.10042. View

17.

Mosharaf M, Reza M, Gov E, Mahumud R, Haque Mollah M . Disclosing Potential Key Genes, Therapeutic Targets and Agents for Non-Small Cell Lung Cancer: Evidence from Integrative Bioinformatics Analysis. Vaccines (Basel). 2022; 10(5). PMC: 9143695. DOI: 10.3390/vaccines10050771. View

18.

Sikder H, Devlin M, Dunlap S, Ryu B, Alani R . Id proteins in cell growth and tumorigenesis. Cancer Cell. 2003; 3(6):525-30. DOI: 10.1016/s1535-6108(03)00141-7. View

19.

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Pineros M . Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2018; 144(8):1941-1953. DOI: 10.1002/ijc.31937. View

20.

Chen J, Hsu Y, Hsu Y, Tseng Y, Liu M, Weng C . Id2 exerts tumor suppressor properties in lung cancer through its effects on cancer cell invasion and migration. Front Oncol. 2022; 12:801300. PMC: 9379288. DOI: 10.3389/fonc.2022.801300. View