LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis
Abstract Although programmed death-ligand 1 (PD-L1) inhibitors have achieved some therapeutic success in breast cancer, their efficacy is limited by low therapeutic response rates, which is closely related to the immune escape of breast cancer cells. Tissue differentiation inducing non-protein codin...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05609-2 |
| _version_ | 1811171482943881216 |
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| author | Qin Wang Guozheng Li Xin Ma Lei Liu Jiena Liu Yanling Yin Hui Li Yihai Chen Xin Zhang Lei Zhang Liyang Sun Jing Ai Shouping Xu |
| author_facet | Qin Wang Guozheng Li Xin Ma Lei Liu Jiena Liu Yanling Yin Hui Li Yihai Chen Xin Zhang Lei Zhang Liyang Sun Jing Ai Shouping Xu |
| author_sort | Qin Wang |
| collection | DOAJ |
| description | Abstract Although programmed death-ligand 1 (PD-L1) inhibitors have achieved some therapeutic success in breast cancer, their efficacy is limited by low therapeutic response rates, which is closely related to the immune escape of breast cancer cells. Tissue differentiation inducing non-protein coding RNA (TINCR), a long non-coding RNA, as an oncogenic gene associated with the progression of various malignant tumors, including breast cancer; however, the role of TINCR in tumor immunity, especially in breast cancer, remains unclear. We confirmed that TINCR upregulated PD-L1 expression in vivo and in vitro, and promoted the progression of breast cancer. Next, we revealed that TINCR knockdown can significantly improve the therapeutic effect of PD-L1 inhibitors in breast cancer in vivo. Mechanistically, TINCR recruits DNMT1 to promote the methylation of miR-199a-5p loci and inhibit its transcription. Furthermore, in the cytoplasm, TINCR potentially acts as a molecular sponge of miR-199a-5p and upregulates the stability of USP20 mRNA through a competing endogenous RNA (ceRNA) regulatory mechanism, thus promoting PD-L1 expression by decreasing its ubiquitination level. IFN-γ stimulation activates STAT1 by phosphorylation, which migrates into the nucleus to promote TINCR transcription. This is the first study to describe the regulatory role of TINCR in breast cancer tumor immunity, broadening the current paradigm of the functional diversity of TINCR in tumor biology. In addition, our study provides new research directions and potential therapeutic targets for PD-L1 inhibitors in breast cancer. |
| first_indexed | 2024-04-10T17:15:45Z |
| format | Article |
| id | doaj.art-0599f9cbed6740339bf6ce19e9f387c1 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T17:15:45Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0599f9cbed6740339bf6ce19e9f387c12023-02-05T12:25:29ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211210.1038/s41419-023-05609-2LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axisQin Wang0Guozheng Li1Xin Ma2Lei Liu3Jiena Liu4Yanling Yin5Hui Li6Yihai Chen7Xin Zhang8Lei Zhang9Liyang Sun10Jing Ai11Shouping Xu12Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical UniversityDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Breast Surgery, Harbin Medical University Cancer HospitalDepartment of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical UniversityDepartment of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical UniversityHeilongjiang Academy of Medical SciencesAbstract Although programmed death-ligand 1 (PD-L1) inhibitors have achieved some therapeutic success in breast cancer, their efficacy is limited by low therapeutic response rates, which is closely related to the immune escape of breast cancer cells. Tissue differentiation inducing non-protein coding RNA (TINCR), a long non-coding RNA, as an oncogenic gene associated with the progression of various malignant tumors, including breast cancer; however, the role of TINCR in tumor immunity, especially in breast cancer, remains unclear. We confirmed that TINCR upregulated PD-L1 expression in vivo and in vitro, and promoted the progression of breast cancer. Next, we revealed that TINCR knockdown can significantly improve the therapeutic effect of PD-L1 inhibitors in breast cancer in vivo. Mechanistically, TINCR recruits DNMT1 to promote the methylation of miR-199a-5p loci and inhibit its transcription. Furthermore, in the cytoplasm, TINCR potentially acts as a molecular sponge of miR-199a-5p and upregulates the stability of USP20 mRNA through a competing endogenous RNA (ceRNA) regulatory mechanism, thus promoting PD-L1 expression by decreasing its ubiquitination level. IFN-γ stimulation activates STAT1 by phosphorylation, which migrates into the nucleus to promote TINCR transcription. This is the first study to describe the regulatory role of TINCR in breast cancer tumor immunity, broadening the current paradigm of the functional diversity of TINCR in tumor biology. In addition, our study provides new research directions and potential therapeutic targets for PD-L1 inhibitors in breast cancer.https://doi.org/10.1038/s41419-023-05609-2 |
| spellingShingle | Qin Wang Guozheng Li Xin Ma Lei Liu Jiena Liu Yanling Yin Hui Li Yihai Chen Xin Zhang Lei Zhang Liyang Sun Jing Ai Shouping Xu LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis Cell Death and Disease |
| title | LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis |
| title_full | LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis |
| title_fullStr | LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis |
| title_full_unstemmed | LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis |
| title_short | LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis |
| title_sort | lncrna tincr impairs the efficacy of immunotherapy against breast cancer by recruiting dnmt1 and downregulating mir 199a 5p via the stat1 tincr usp20 pd l1 axis |
| url | https://doi.org/10.1038/s41419-023-05609-2 |
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