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

Fan Sun; Liwen Li; Pengrong Yan; Jingjiao Zhou; Steven D Shapiro; Gutian Xiao; Zhaoxia Qu

doi:10.1038/s41467-019-13331-x

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

Nat Commun. 2019 Nov 22;10(1):5324. doi: 10.1038/s41467-019-13331-x.

Authors

Fan Sun^{1

2}, Liwen Li^{1

2}, Pengrong Yan^{1

2

3}, Jingjiao Zhou^{1

2}, Steven D Shapiro⁴, Gutian Xiao^{5

6}, Zhaoxia Qu^{7

8}

Affiliations

¹ UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
² Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
³ Chemical Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁴ Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
⁵ UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. xiaog2@upmc.edu.
⁶ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. xiaog2@upmc.edu.
⁷ UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. quz@upmc.edu.
⁸ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. quz@upmc.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Animals
Antineoplastic Agents, Immunological / therapeutic use
B7-H1 Antigen / antagonists & inhibitors
Cell Line, Tumor
DNA Methylation
Disease Models, Animal
Drug Resistance, Neoplasm / genetics
Epigenetic Repression / genetics*
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Genes, Tumor Suppressor
Humans
LIM Domain Proteins / genetics*
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Mice
Mice, Knockout
Microfilament Proteins / genetics*
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Promoter Regions, Genetic
Proto-Oncogene Proteins p21(ras) / genetics
STAT3 Transcription Factor / genetics
Transcription Factor RelA / genetics

Substances

Adaptor Proteins, Signal Transducing
Antineoplastic Agents, Immunological
B7-H1 Antigen
LIM Domain Proteins
Microfilament Proteins
PDLIM2 protein, human
Pdlim2 protein, mouse
Programmed Cell Death 1 Receptor
Rela protein, mouse
STAT3 Transcription Factor
Stat3 protein, mouse
Transcription Factor RelA
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Grants and funding

R01 CA172090/CA/NCI NIH HHS/United States