TY - JOUR
T1 - ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer
AU - Shukla, Vivek
AU - Rao, Mahadev
AU - Zhang, Hongen
AU - Beers, Jeanette
AU - Wangsa, Darawalee
AU - Wangsa, Danny
AU - Buishand, Floryne O.
AU - Wang, Yonghong
AU - Yu, Zhiya
AU - Stevenson, Holly S.
AU - Reardon, Emily S.
AU - McLoughlin, Kaitlin C.
AU - Kaufman, Andrew S.
AU - Payabyab, Eden C.
AU - Hong, Julie A.
AU - Zhang, Mary
AU - Davis, Sean
AU - Edelman, Daniel
AU - Chen, Guokai
AU - Miettinen, Markku M.
AU - Restifo, Nicholas P.
AU - Ried, Thomas
AU - Meltzer, Paul A.
AU - Schrump, David S.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-0570
DO - 10.1158/0008-5472.CAN-17-0570
M3 - Article
C2 - 28935813
AN - SCOPUS:85033804364
SN - 0008-5472
VL - 77
SP - 6267
EP - 6281
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -
