NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification

Yongkang Yang; Chelsey Chen; Qiaozhu Zuo; Haiquan Lu; Shaima Salman; Yajing Lyu; Tina Yi Ting Huang; Elizabeth E. Wicks; Walter Jackson; Emmanuel Datan; Ru Wang; Yufeng Wang; Nguyet Le; Yayun Zhu; Wenxin Qin; Gregg L. Semenza

doi:10.1126/sciadv.abo5000

NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification

Yongkang Yang, Chelsey Chen, Qiaozhu Zuo, Haiquan Lu, Shaima Salman, Yajing Lyu, Tina Yi Ting Huang, Elizabeth E. Wicks, Walter Jackson, Emmanuel Datan, Ru Wang, Yufeng Wang, Nguyet Le, Yayun Zhu, Wenxin Qin, Gregg L. Semenza

School of Medicine

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

Abstract

Hypoxia is a key characteristic of the breast cancer microenvironment that promotes expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and is associated with poor patient outcome. HIF-1 increases the expression or activity of stem cell pluripotency factors, which control breast cancer stem cell (BCSC) specification and are required for cancer metastasis. Here, we identify nuclear prelamin A recognition factor (NARF) as a hypoxia-inducible, HIF-1 target gene in human breast cancer cells. NARF functions as an essential coactivator by recruiting the histone demethylase KDM6A to OCT4 bound to genes encoding the pluripotency factors NANOG, KLF4, and SOX2, leading to demethylation of histone H3 trimethylated at lysine-27 (H3K27me3), thereby increasing the expression of NANOG, KLF4, and SOX2, which, together with OCT4, mediate BCSC specification. Knockdown of NARF significantly decreased the BCSC population in vitro and markedly impaired tumor initiation capacity and lung metastasis in orthotopic mouse models.

Original language	English (US)
Article number	abo5000
Journal	Science Advances
Volume	8
Issue number	49
DOIs	https://doi.org/10.1126/sciadv.abo5000
State	Published - 2022

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title = "NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification",

abstract = "Hypoxia is a key characteristic of the breast cancer microenvironment that promotes expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and is associated with poor patient outcome. HIF-1 increases the expression or activity of stem cell pluripotency factors, which control breast cancer stem cell (BCSC) specification and are required for cancer metastasis. Here, we identify nuclear prelamin A recognition factor (NARF) as a hypoxia-inducible, HIF-1 target gene in human breast cancer cells. NARF functions as an essential coactivator by recruiting the histone demethylase KDM6A to OCT4 bound to genes encoding the pluripotency factors NANOG, KLF4, and SOX2, leading to demethylation of histone H3 trimethylated at lysine-27 (H3K27me3), thereby increasing the expression of NANOG, KLF4, and SOX2, which, together with OCT4, mediate BCSC specification. Knockdown of NARF significantly decreased the BCSC population in vitro and markedly impaired tumor initiation capacity and lung metastasis in orthotopic mouse models.",

author = "Yongkang Yang and Chelsey Chen and Qiaozhu Zuo and Haiquan Lu and Shaima Salman and Yajing Lyu and Huang, {Tina Yi Ting} and Wicks, {Elizabeth E.} and Walter Jackson and Emmanuel Datan and Ru Wang and Yufeng Wang and Nguyet Le and Yayun Zhu and Wenxin Qin and Semenza, {Gregg L.}",

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year = "2022",

doi = "10.1126/sciadv.abo5000",

language = "English (US)",

volume = "8",

journal = "Science Advances",

issn = "2375-2548",

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T1 - NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification

AU - Yang, Yongkang

AU - Chen, Chelsey

AU - Zuo, Qiaozhu

AU - Lu, Haiquan

AU - Salman, Shaima

AU - Lyu, Yajing

AU - Huang, Tina Yi Ting

AU - Wicks, Elizabeth E.

AU - Jackson, Walter

AU - Datan, Emmanuel

AU - Wang, Ru

AU - Wang, Yufeng

AU - Le, Nguyet

AU - Zhu, Yayun

AU - Qin, Wenxin

AU - Semenza, Gregg L.

PY - 2022

Y1 - 2022

N2 - Hypoxia is a key characteristic of the breast cancer microenvironment that promotes expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and is associated with poor patient outcome. HIF-1 increases the expression or activity of stem cell pluripotency factors, which control breast cancer stem cell (BCSC) specification and are required for cancer metastasis. Here, we identify nuclear prelamin A recognition factor (NARF) as a hypoxia-inducible, HIF-1 target gene in human breast cancer cells. NARF functions as an essential coactivator by recruiting the histone demethylase KDM6A to OCT4 bound to genes encoding the pluripotency factors NANOG, KLF4, and SOX2, leading to demethylation of histone H3 trimethylated at lysine-27 (H3K27me3), thereby increasing the expression of NANOG, KLF4, and SOX2, which, together with OCT4, mediate BCSC specification. Knockdown of NARF significantly decreased the BCSC population in vitro and markedly impaired tumor initiation capacity and lung metastasis in orthotopic mouse models.

AB - Hypoxia is a key characteristic of the breast cancer microenvironment that promotes expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and is associated with poor patient outcome. HIF-1 increases the expression or activity of stem cell pluripotency factors, which control breast cancer stem cell (BCSC) specification and are required for cancer metastasis. Here, we identify nuclear prelamin A recognition factor (NARF) as a hypoxia-inducible, HIF-1 target gene in human breast cancer cells. NARF functions as an essential coactivator by recruiting the histone demethylase KDM6A to OCT4 bound to genes encoding the pluripotency factors NANOG, KLF4, and SOX2, leading to demethylation of histone H3 trimethylated at lysine-27 (H3K27me3), thereby increasing the expression of NANOG, KLF4, and SOX2, which, together with OCT4, mediate BCSC specification. Knockdown of NARF significantly decreased the BCSC population in vitro and markedly impaired tumor initiation capacity and lung metastasis in orthotopic mouse models.

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NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification

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