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 Stevenson; Emily Reardon; Kaitlin C McLoughlin; Andrew Kaufman; Eden Payabyab; Julie A Hong; Mary Zhang; Sean R Davis; Daniel C Edelman; Guokai Chen; Markku Miettinen; Nicholas Restfo; Thomas Ried; Paul S Meltzer; David S Schrump

doi: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

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

Research output: Contribution to journal › Article › Academic › peer-review

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 iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC 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-iPSC, 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 language	English
Pages (from-to)	6267-6281
Journal	Cancer Research
Volume	77
Issue number	22
Early online date	21 Sept 2017
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-0570
Publication status	Published - Nov 2017

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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., Reardon, E., McLoughlin, K. C., Kaufman, A., Payabyab, E., Hong, J. A., Zhang, M., Davis, S. R., Edelman, D. C., 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

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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 iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC 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-iPSC, 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 Holly Stevenson and Emily Reardon and McLoughlin, {Kaitlin C} and Andrew Kaufman and Eden Payabyab and Hong, {Julie A} and Mary Zhang and Davis, {Sean R} and Edelman, {Daniel C} and Guokai Chen and Markku Miettinen and Nicholas Restfo and Thomas Ried and Meltzer, {Paul S} and Schrump, {David S}",

note = "Copyright {\textcopyright}2017, American Association for Cancer Research.",

year = "2017",

month = nov,

doi = "10.1158/0008-5472.CAN-17-0570",

language = "English",

volume = "77",

pages = "6267--6281",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "22",

}

Shukla, V, Rao, M, Zhang, H, Beers, J, Wangsa, D, Wangsa, D, Buishand, FO, Wang, Y, Yu, Z, Stevenson, H, Reardon, E, McLoughlin, KC, Kaufman, A, Payabyab, E, Hong, JA, Zhang, M, Davis, SR, Edelman, DC, Chen, G, Miettinen, M, Restfo, N, Ried, T, Meltzer, PS & 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

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

AU - Reardon, Emily

AU - McLoughlin, Kaitlin C

AU - Kaufman, Andrew

AU - Payabyab, Eden

AU - Hong, Julie A

AU - Zhang, Mary

AU - Davis, Sean R

AU - Edelman, Daniel C

AU - Chen, Guokai

AU - Miettinen, Markku

AU - Restfo, Nicholas

AU - Ried, Thomas

AU - Meltzer, Paul S

AU - Schrump, David S

PY - 2017/11

Y1 - 2017/11

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 iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC 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-iPSC, 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 iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC 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-iPSC, 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.

U2 - 10.1158/0008-5472.CAN-17-0570

DO - 10.1158/0008-5472.CAN-17-0570

M3 - Article

C2 - 28935813

SN - 0008-5472

VL - 77

SP - 6267

EP - 6281

JO - Cancer Research

JF - Cancer Research

IS - 22

ER -

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

Abstract

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