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. Miettinen & 4 others Nicholas P. Restifo, Thomas Ried, Paul A. Meltzer, David S. Schrump

Research output: Contribution to journalArticle

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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

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Small Cell Lung Carcinoma
Epithelial Cells
Epigenomics
Lung
Induced Pluripotent Stem Cells
Teratoma
Therapeutics
Lung Neoplasms
Carcinogenesis
Growth
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Shukla, Vivek ; Rao, Mahadev ; Zhang, Hongen ; Beers, Jeanette ; Wangsa, Darawalee ; Wangsa, Danny ; Buishand, Floryne O. ; Wang, Yonghong ; Yu, Zhiya ; Stevenson, Holly S. ; Reardon, Emily S. ; McLoughlin, Kaitlin C. ; Kaufman, Andrew S. ; Payabyab, Eden C. ; Hong, Julie A. ; Zhang, Mary ; Davis, Sean ; Edelman, Daniel ; Chen, Guokai ; Miettinen, Markku M. ; Restifo, Nicholas P. ; Ried, Thomas ; Meltzer, Paul A. ; Schrump, David S. / ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer. In: Cancer Research. 2017 ; Vol. 77, No. 22. pp. 6267-6281.
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title = "ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer",
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.",
author = "Vivek Shukla and Mahadev Rao and Hongen Zhang and Jeanette Beers and Darawalee Wangsa and Danny Wangsa and Buishand, {Floryne O.} and Yonghong Wang and Zhiya Yu and Stevenson, {Holly S.} and Reardon, {Emily S.} and McLoughlin, {Kaitlin C.} and Kaufman, {Andrew S.} and Payabyab, {Eden C.} and Hong, {Julie A.} and Mary Zhang and Sean Davis and Daniel Edelman and Guokai Chen and Miettinen, {Markku M.} and Restifo, {Nicholas P.} and Thomas Ried and Meltzer, {Paul A.} and Schrump, {David S.}",
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Shukla, V, Rao, M, Zhang, H, Beers, J, Wangsa, D, Wangsa, D, Buishand, FO, Wang, Y, Yu, Z, Stevenson, HS, Reardon, ES, McLoughlin, KC, Kaufman, AS, Payabyab, EC, Hong, JA, Zhang, M, Davis, S, Edelman, D, Chen, G, Miettinen, MM, Restifo, NP, Ried, T, Meltzer, PA & Schrump, DS 2017, 'ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer', Cancer Research, vol. 77, no. 22, pp. 6267-6281. https://doi.org/10.1158/0008-5472.CAN-17-0570

ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer. / Shukla, Vivek; Rao, Mahadev; Zhang, Hongen; Beers, Jeanette; Wangsa, Darawalee; Wangsa, Danny; Buishand, Floryne O.; Wang, Yonghong; Yu, Zhiya; Stevenson, Holly S.; Reardon, Emily S.; McLoughlin, Kaitlin C.; Kaufman, Andrew S.; Payabyab, Eden C.; Hong, Julie A.; Zhang, Mary; Davis, Sean; Edelman, Daniel; Chen, Guokai; Miettinen, Markku M.; Restifo, Nicholas P.; Ried, Thomas; Meltzer, Paul A.; Schrump, David S.

In: Cancer Research, Vol. 77, No. 22, 15.11.2017, p. 6267-6281.

Research output: Contribution to journalArticle

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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.

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.

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