ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer

Vivek Shukla, Mahadev Rao, Hongen Zhang, Jeanette Beers, Darawalee Wangsa, Danny Wangsa, Floryne O. Buishand, Yonghong Wang, Zhiya Yu, Holly S. Stevenson, Emily S. Reardon, Kaitlin C. McLoughlin, Andrew S. Kaufman, Eden C. Payabyab, Julie A. Hong, Mary Zhang, Sean Davis, Daniel Edelman, Guokai Chen, Markku M. MiettinenNicholas P. Restifo, Thomas Ried, Paul A. Meltzer, David S. Schrump

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6267-6281
Number of pages15
JournalCancer Research
Volume77
Issue number22
DOIs
Publication statusPublished - 15-11-2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Shukla, V., Rao, M., Zhang, H., Beers, J., Wangsa, D., Wangsa, D., Buishand, F. O., Wang, Y., Yu, Z., Stevenson, H. S., Reardon, E. S., McLoughlin, K. C., Kaufman, A. S., Payabyab, E. C., Hong, J. A., Zhang, M., Davis, S., Edelman, D., Chen, G., ... Schrump, D. S. (2017). ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer. Cancer Research, 77(22), 6267-6281. https://doi.org/10.1158/0008-5472.CAN-17-0570