Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Xuxu Sun; Sam C. Wang; Yonglong Wei; Xin Luo; Yuemeng Jia; Lin Li; Purva Gopal; Min Zhu; Ibrahim Nassour; Jen Chieh Chuang; Thomas Maples; Cemre Celen; Liem H. Nguyen; Linwei Wu; Shunjun Fu; Weiping Li; Lijian Hui; Feng Tian; Yuan Ji; Shuyuan Zhang; Mahsa Sorouri; Tae Hyun Hwang; Lynda Letzig; Laura James; Zixi Wang; Adam C. Yopp; Amit G. Singal; Hao Zhu

doi:10.1016/j.ccell.2017.10.007

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan ZhangMahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu

Artificial Intelligence and Informatics

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

Abstract

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer. Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.

Original language	English (US)
Pages (from-to)	574-589.e6
Journal	Cancer cell
Volume	32
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2017.10.007
State	Published - Nov 13 2017

Keywords

ARID1A
SWI/SNF chromatin-remodeling complex
epigenetics
hepatocellular carcinoma
metastasis
mouse models

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2017.10.007

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Sun, X., Wang, S. C., Wei, Y., Luo, X., Jia, Y., Li, L., Gopal, P., Zhu, M., Nassour, I., Chuang, J. C., Maples, T., Celen, C., Nguyen, L. H., Wu, L., Fu, S., Li, W., Hui, L., Tian, F., Ji, Y., ... Zhu, H. (2017). Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer cell, 32(5), 574-589.e6. https://doi.org/10.1016/j.ccell.2017.10.007

Sun, X, Wang, SC, Wei, Y, Luo, X, Jia, Y, Li, L, Gopal, P, Zhu, M, Nassour, I, Chuang, JC, Maples, T, Celen, C, Nguyen, LH, Wu, L, Fu, S, Li, W, Hui, L, Tian, F, Ji, Y, Zhang, S, Sorouri, M, Hwang, TH, Letzig, L, James, L, Wang, Z, Yopp, AC, Singal, AG & Zhu, H 2017, 'Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer', Cancer cell, vol. 32, no. 5, pp. 574-589.e6. https://doi.org/10.1016/j.ccell.2017.10.007

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title = "Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer",

abstract = "ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer. Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.",

keywords = "ARID1A, SWI/SNF chromatin-remodeling complex, epigenetics, hepatocellular carcinoma, metastasis, mouse models",

author = "Xuxu Sun and Wang, {Sam C.} and Yonglong Wei and Xin Luo and Yuemeng Jia and Lin Li and Purva Gopal and Min Zhu and Ibrahim Nassour and Chuang, {Jen Chieh} and Thomas Maples and Cemre Celen and Nguyen, {Liem H.} and Linwei Wu and Shunjun Fu and Weiping Li and Lijian Hui and Feng Tian and Yuan Ji and Shuyuan Zhang and Mahsa Sorouri and Hwang, {Tae Hyun} and Lynda Letzig and Laura James and Zixi Wang and Yopp, {Adam C.} and Singal, {Amit G.} and Hao Zhu",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = nov,

day = "13",

doi = "10.1016/j.ccell.2017.10.007",

language = "English (US)",

volume = "32",

pages = "574--589.e6",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

AU - Sun, Xuxu

AU - Wang, Sam C.

AU - Wei, Yonglong

AU - Luo, Xin

AU - Jia, Yuemeng

AU - Li, Lin

AU - Gopal, Purva

AU - Zhu, Min

AU - Nassour, Ibrahim

AU - Chuang, Jen Chieh

AU - Maples, Thomas

AU - Celen, Cemre

AU - Nguyen, Liem H.

AU - Wu, Linwei

AU - Fu, Shunjun

AU - Li, Weiping

AU - Hui, Lijian

AU - Tian, Feng

AU - Ji, Yuan

AU - Zhang, Shuyuan

AU - Sorouri, Mahsa

AU - Hwang, Tae Hyun

AU - Letzig, Lynda

AU - James, Laura

AU - Wang, Zixi

AU - Yopp, Adam C.

AU - Singal, Amit G.

AU - Zhu, Hao

PY - 2017/11/13

Y1 - 2017/11/13

N2 - ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer. Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.

AB - ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer. Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.

KW - ARID1A

KW - SWI/SNF chromatin-remodeling complex

KW - epigenetics

KW - hepatocellular carcinoma

KW - metastasis

KW - mouse models

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DO - 10.1016/j.ccell.2017.10.007

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AN - SCOPUS:85033691958

SN - 1535-6108

VL - 32

SP - 574-589.e6

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Abstract

Keywords

ASJC Scopus subject areas

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