High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts

Arik Bernard Schulze; Daniela Vanessa Wenge; Georg Evers; Birthe Heitkötter; Annalen Bleckmann; Lars Henning Schmidt; Michael Mohr; Wolfgang Hartmann; Maria Francisca Arteaga; Jan-Henrik Mikesch

doi:10.21037/tlcr-22-714

High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts

Transl Lung Cancer Res. 2023 Apr 28;12(4):727-741. doi: 10.21037/tlcr-22-714. Epub 2023 Mar 23.

Authors

Arik Bernard Schulze^{1

2}, Daniela Vanessa Wenge^{1

3}, Georg Evers^{1

2}, Birthe Heitkötter^{2

4}, Annalen Bleckmann^{1

2}, Lars Henning Schmidt^{5

6}, Michael Mohr^{1

2}, Wolfgang Hartmann^{2

4}, Maria Francisca Arteaga^#¹, Jan-Henrik Mikesch^#^{1

2}

Affiliations

¹ Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, Muenster, Germany.
² West German Cancer Center, University Hospital Muenster, Muenster, Germany.
³ Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA, USA.
⁴ Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany.
⁵ IV. Medical Department, Pulmonary Medicine and Thoracic Oncology, Klinikum Ingolstadt, Ingolstadt, Germany.
⁶ Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

^# Contributed equally.

Abstract

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and its most important risk factor is tobacco smoking. While smoking is associated with inferior outcome in NSCLC patients, smoking also correlates with a higher tumor mutational burden. In contrast to adenocarcinomas (ADC) of non-smokers, that frequently harbor targetable gain-of-function mutations, NSCLC smokers largely present with non-targetable loss-of-function mutations of genes associated with DNA-damage repair. The transcription factor Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1) is a widely expressed bipotential stabilizer of repressed and inducible transcriptional states and frequently deregulated in cancer.

Methods: Via immunohistochemistry, we evaluated POU2F1 protein expression on a tissue micro array of 217 operable stage I-III NSCLC patients. Findings were reproduced in a gene expression database of 1144 NSCLC patients, filtered for POU2F1 mRNA expression. After retroviral overexpression of POU2F1 in A549 cells, we evaluated for clonogenic growth and proliferation. Additionally, CRISPR-Cas9 mediated POU2F1 knockdown in A549 cells was likewise analyzed.

Results: High protein expression of POU2F1 in 217 NSCLC patients resulted in improved outcome of smokers with ADC [hazard ratio (HR) 0.30 (0.09-0.99), P=0.035]. Moreover, gene expression analysis confirmed favorable outcome of high POU2F1 mRNA expression in smokers with ADC [HR 0.41 (0.24-0.69), P<0.001]. Other than that, retrovirally induced overexpression of POU2F1 in A549 cells significantly reduced both, clonogenic growth as well as proliferation of NSCLC cells, whereas CRISPR-Cas9 mediated knockdown of the protein did not have any impact.

Conclusions: Our data suggest that high expression of POU2F1 mediates a less aggressive cancer phenotype in smokers with ADC NSCLC. Pharmacological induction of genes and signaling pathways controlled by POU2F1 may provide novel avenues for future targeted NSCLC therapies in smokers.

Keywords: Non-small cell lung cancer (NSCLC); Oct1; Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1); adenocarcinoma; smoking.