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Cancer Res. 2017 Nov 15;77(22):6267-6281. doi: 10.1158/0008-5472.CAN-17-0570. Epub 2017 Sep 21.

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

Author information

1
Thoracic Epigenetics Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Rockville, Maryland.
2
Genetics Branch, Center for Cancer Research, NCI, Rockville, Maryland.
3
NHLBI iPSC Core, NIH, Bethesda, Maryland.
4
Laboratory of Pathology, Center for Cancer Research, NCI, Rockville, Maryland.
5
Surgery Branch, Center for Cancer Research, NCI, Rockville, Maryland.
6
Thoracic Epigenetics Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Rockville, Maryland. David_Schrump@nih.gov.

Abstract

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR.

PMID:
28935813
PMCID:
PMC5690859
DOI:
10.1158/0008-5472.CAN-17-0570
[Indexed for MEDLINE]
Free PMC Article

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