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Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance

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...

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Autores principales: Sun, Fan, Li, Liwen, Yan, Pengrong, Zhou, Jingjiao, Shapiro, Steven D., Xiao, Gutian, Qu, Zhaoxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876573/
https://www.ncbi.nlm.nih.gov/pubmed/31757943
http://dx.doi.org/10.1038/s41467-019-13331-x
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author Sun, Fan
Li, Liwen
Yan, Pengrong
Zhou, Jingjiao
Shapiro, Steven D.
Xiao, Gutian
Qu, Zhaoxia
author_facet Sun, Fan
Li, Liwen
Yan, Pengrong
Zhou, Jingjiao
Shapiro, Steven D.
Xiao, Gutian
Qu, Zhaoxia
author_sort Sun, Fan
collection PubMed
description 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.
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spelling pubmed-68765732019-11-26 Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance Sun, Fan Li, Liwen Yan, Pengrong Zhou, Jingjiao Shapiro, Steven D. Xiao, Gutian Qu, Zhaoxia Nat Commun Article 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. Nature Publishing Group UK 2019-11-22 /pmc/articles/PMC6876573/ /pubmed/31757943 http://dx.doi.org/10.1038/s41467-019-13331-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sun, Fan
Li, Liwen
Yan, Pengrong
Zhou, Jingjiao
Shapiro, Steven D.
Xiao, Gutian
Qu, Zhaoxia
Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title_full Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title_fullStr Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title_full_unstemmed Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title_short Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance
title_sort causative role of pdlim2 epigenetic repression in lung cancer and therapeutic resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876573/
https://www.ncbi.nlm.nih.gov/pubmed/31757943
http://dx.doi.org/10.1038/s41467-019-13331-x
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