Nature communications, 2019-11, Vol.10 (1), p.5324-13, Article 5324
2019
Details
- Autor(en) / Beteiligte
- Titel
- Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
- Ist Teil von
- Nature communications, 2019-11, Vol.10 (1), p.5324-13, Article 5324
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Most cancers are resistant to anti-PD-1/PD-L1 and chemotherapy. Herein we identify PDLIM2 as a tumor suppressor particularly important for lung cancer therapeutic responses. While PDLIM2 is epigenetically repressed in human lung cancer, associating with therapeutic resistance and poor prognosis, its global or lung epithelial-specific deletion in mice causes increased lung cancer development, chemoresistance, and complete resistance to anti-PD-1 and epigenetic drugs. PDLIM2 epigenetic restoration or ectopic expression shows antitumor activity, and synergizes with anti-PD-1, notably, with chemotherapy for complete remission of most lung cancers. Mechanistically, through repressing NF-κB/RelA and STAT3, PDLIM2 increases expression of genes involved in antigen presentation and T-cell activation while repressing multidrug resistance genes and cancer-related genes, thereby rendering cancer cells vulnerable to immune attacks and therapies. We identify PDLIM2-independent PD-L1 induction by chemotherapeutic and epigenetic drugs as another mechanism for their synergy with anti-PD-1. These findings establish a rationale to use combination therapies for cancer treatment.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-13331-xTitel-ID: cdi_doaj_primary_oai_doaj_org_article_1d400ac3bbf44a7799867ab4feea7bfd
- Format
- –
- Schlagworte
- Adaptor Proteins, Signal Transducing - genetics, Animals, Anticancer properties, Antigen presentation, Antigens, Antineoplastic Agents, Immunological - therapeutic use, Antitumor activity, B7-H1 Antigen - antagonists & inhibitors, Cancer therapies, Cell activation, Cell Line, Tumor, Chemoresistance, Chemotherapy, Clonal deletion, Disease Models, Animal, DNA Methylation, Drug development, Drug Resistance, Neoplasm - genetics, Drugs, Ectopic expression, Epigenetic Repression - genetics, Epigenetics, Gene expression, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genes, Genes, Tumor Suppressor, Humans, Immunosuppressive agents, LIM Domain Proteins - genetics, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - genetics, Lymphocytes T, Mice, Mice, Knockout, Microfilament Proteins - genetics, Multidrug resistance, NF-κB protein, PD-1 protein, PD-L1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Promoter Regions, Genetic, Proto-Oncogene Proteins p21(ras) - genetics, RelA protein, Remission, Restoration, Stat3 protein, STAT3 Transcription Factor - genetics, Transcription Factor RelA - genetics, Tumor suppressor genes