Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription Implication of CIITA in tumor and metastasis development
- Resource Type
- Authors
- Cristina Broceño; Antonia Vinyals; Pedro Alía; Janet E. Price; Marc Adrover; Bo Shi; Carme Gelpi; Feisong Chen; Angels Fabra
- Source
- The international journal of biochemistrycell biology. 38(4)
- Subject
- CIITA Gene
Mice, Nude
chemical and pharmacologic phenomena
Apoptosis
Breast Neoplasms
Biology
Major histocompatibility complex
Response Elements
Biochemistry
Transactivation
Mice
Antigen
Cell Line, Tumor
CIITA
Animals
Humans
Neoplasm Metastasis
Regulation of gene expression
MHC class II
Histocompatibility Antigens Class II
Nuclear Proteins
Cell Biology
Neoplasms, Experimental
DNA Methylation
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Killer Cells, Natural
DNA methylation
biology.protein
Cancer research
Trans-Activators
Female
Neoplasm Transplantation
- Language
- ISSN
- 1357-2725
We analyzed the differential gene expression between variants of MDA-MB-435 human breast cancer cell line that share an identical genetic background but have different metastatic ability. The major histocompatibility complex class II was found down-regulated in highly metastatic cells and correlated with MHC transactivator (CIITA) expression. Constitutive CIITA expression observed in poorly metastatic is driven by promoters III and IV of CIITA gene. Conversely, both promoters were ineffective in highly metastatic cells. The MHC class II and CIITA expression was restored in these cells upon stimulation with IFNgamma or by the treatment with a hypomethylating agent. Both treatments induced USF-1 and IRF binding complexes to promoter IV but only IFNgamma induced the binding of 435-Lung2 nuclear proteins to an ARE-1 site at the promoter III. Neither Southern blot nor bisulfite sequencing of promoter IV demonstrated strong hypermethylation of this promoter at the IFNgamma-responsive elements such as GAS, E-box or IRF-1. We suggest that partial or hemimethylation of promoter IV is sufficient to silence the CIITA expression in highly metastatic cells and that this epigenetic mechanism is responsible for the lack of MHC-II expression. Forced CIITA expression restored the MHC-II antigen expression in 435-Lung2 cells and abrogates spontaneous lung metastasis in both SCID and nude mice but also affected the tumorigenicity in nude mice. The increase in NK cell infiltration in nude mice bearing CIITA-tumors correlated with sign of tumor cell apoptosis and the increase in the number of NK cells in the spleens, suggesting that NK cells might be responsible for the observed antitumor activity.