Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells
Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like <i>Peroxiredoxin 6</i> (<i>Prdx6</i>) and affects cellular homeostasis. We previously observed that dose le...
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MDPI AG
2019-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/10/1159 |
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| author | Bhavana Chhunchha Eri Kubo Dhirendra P. Singh |
| author_facet | Bhavana Chhunchha Eri Kubo Dhirendra P. Singh |
| author_sort | Bhavana Chhunchha |
| collection | DOAJ |
| description | Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like <i>Peroxiredoxin 6</i> (<i>Prdx6</i>) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN (>6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of <i>Prdx6</i> expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-C<sup>A/G</sup>CCC-3) in the <i>Prdx6</i> promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as <i>Prdx6</i> via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy. |
| first_indexed | 2024-03-12T07:08:42Z |
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| language | English |
| last_indexed | 2024-03-12T07:08:42Z |
| publishDate | 2019-09-01 |
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| spelling | doaj.art-00443c10b74b474d97fbba6406abc90a2023-09-02T23:12:23ZengMDPI AGCells2073-44092019-09-01810115910.3390/cells8101159cells8101159Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of CellsBhavana Chhunchha0Eri Kubo1Dhirendra P. Singh2Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Ophthalmology, Kanazawa Medical University, Ishikawa 9200293, JapanDepartment of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USASulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like <i>Peroxiredoxin 6</i> (<i>Prdx6</i>) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN (>6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of <i>Prdx6</i> expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-C<sup>A/G</sup>CCC-3) in the <i>Prdx6</i> promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as <i>Prdx6</i> via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy.https://www.mdpi.com/2073-4409/8/10/1159oxidative stresssulforaphaneprdx6nrf2klf9antioxidants |
| spellingShingle | Bhavana Chhunchha Eri Kubo Dhirendra P. Singh Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells Cells oxidative stress sulforaphane prdx6 nrf2 klf9 antioxidants |
| title | Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells |
| title_full | Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells |
| title_fullStr | Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells |
| title_full_unstemmed | Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells |
| title_short | Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells |
| title_sort | sulforaphane induced klf9 prdx6 axis acts as a molecular switch to control redox signaling and determines fate of cells |
| topic | oxidative stress sulforaphane prdx6 nrf2 klf9 antioxidants |
| url | https://www.mdpi.com/2073-4409/8/10/1159 |
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