TY - JOUR
T1 - Chronic arsenic exposure enhances metastatic potential via NRF2-mediated upregulation of SOX9
AU - Schmidlin, Cody J.
AU - Zeng, Tao
AU - Liu, Pengfei
AU - Wei, Yongyi
AU - Dodson, Matthew
AU - Chapman, Eli
AU - Zhang, Donna D.
N1 - Funding Information:
The authors are funded by the following National Institutes of Health grants: T32ES007091 [C.J.S.], R35ES031575 [D.D.Z.], and P42ES004940 [D.D.Z.].
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Chronic low dose arsenic exposure continues to be a worldwide health concern because of its prevalence and link to increased cancer risk, including non-small cell lung cancer (NSCLC). Mortality of NSCLC patients increases with the development of a metastatic lesion compared to when the tumor is localized; however, the exact mechanism for what causes NSCLC cells to metastasize in the context of environmental toxicant exposure has yet to be fully elucidated. One proposed contributor to metastasis in NSCLC is nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor with known oncogenic properties that has proved to be critical for arsenic carcinogenesis. Here, we demonstrate that chronic arsenic exposure enhances the invasive and migratory capacity of immortalized lung epithelial cells via NRF2-dependent upregulation of SRY-box 9 (SOX9), another transcription factor linked with cell proliferation, epithelial-mesenchymal transition, and metastasis. We identified a functional antioxidant response element (ARE) in the promoter region of SOX9, suggesting that it is an NRF2 target gene, with mutation of the ARE preventing NRF2 binding. Pharmacological induction or inhibition of NRF2 increased or decreased SOX9 expression, respectively. Furthermore, we demonstrate that hyperactivation of NRF2 via knockout of Kelch-like ECH-associated protein 1 (KEAP1), its negative regulator, contributes to proliferation; while, inhibition of NRF2 or direct knockdown of SOX9 slowed the ability of NSCLC cells to proliferate, migrate, and invade. Overall, this study suggests that NRF2-mediated SOX9 upregulation can contribute to the metastatic potential of both environmentally and genetically driven lung tumors.
AB - Chronic low dose arsenic exposure continues to be a worldwide health concern because of its prevalence and link to increased cancer risk, including non-small cell lung cancer (NSCLC). Mortality of NSCLC patients increases with the development of a metastatic lesion compared to when the tumor is localized; however, the exact mechanism for what causes NSCLC cells to metastasize in the context of environmental toxicant exposure has yet to be fully elucidated. One proposed contributor to metastasis in NSCLC is nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor with known oncogenic properties that has proved to be critical for arsenic carcinogenesis. Here, we demonstrate that chronic arsenic exposure enhances the invasive and migratory capacity of immortalized lung epithelial cells via NRF2-dependent upregulation of SRY-box 9 (SOX9), another transcription factor linked with cell proliferation, epithelial-mesenchymal transition, and metastasis. We identified a functional antioxidant response element (ARE) in the promoter region of SOX9, suggesting that it is an NRF2 target gene, with mutation of the ARE preventing NRF2 binding. Pharmacological induction or inhibition of NRF2 increased or decreased SOX9 expression, respectively. Furthermore, we demonstrate that hyperactivation of NRF2 via knockout of Kelch-like ECH-associated protein 1 (KEAP1), its negative regulator, contributes to proliferation; while, inhibition of NRF2 or direct knockdown of SOX9 slowed the ability of NSCLC cells to proliferate, migrate, and invade. Overall, this study suggests that NRF2-mediated SOX9 upregulation can contribute to the metastatic potential of both environmentally and genetically driven lung tumors.
KW - Arsenic
KW - Cancer
KW - Metastasis
KW - NRF2
KW - NSCLC
KW - SOX9
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U2 - 10.1016/j.taap.2020.115138
DO - 10.1016/j.taap.2020.115138
M3 - Article
C2 - 32682831
AN - SCOPUS:85088375819
SN - 0041-008X
VL - 402
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
M1 - 115138
ER -