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ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2
Maowu Luo, … , Yingfei Wang, Weibo Luo
Maowu Luo, … , Yingfei Wang, Weibo Luo
Published January 23, 2024
Citation Information: J Clin Invest. 2024;134(6):e171166. https://doi.org/10.1172/JCI171166.
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ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2

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Abstract

Breast cancer stem cells (BCSCs) mitigate oxidative stress to maintain their viability and plasticity. However, the regulatory mechanism of oxidative stress in BCSCs remains unclear. We recently found that the histone reader ZMYND8 was upregulated in BCSCs. Here, we showed that ZMYND8 reduced ROS and iron to inhibit ferroptosis in aldehyde dehydrogenase–high (ALDHhi) BCSCs, leading to BCSC expansion and tumor initiation in mice. The underlying mechanism involved a two-fold posttranslational regulation of nuclear factor erythroid 2–related factor 2 (NRF2). ZMYND8 increased stability of NRF2 protein through KEAP1 silencing. On the other hand, ZMYND8 interacted with and recruited NRF2 to the promoters of antioxidant genes to enhance gene transcription in mammospheres. NRF2 phenocopied ZMYND8 to enhance BCSC stemness and tumor initiation by inhibiting ROS and ferroptosis. Loss of NRF2 counteracted ZMYND8’s effects on antioxidant genes and ROS in mammospheres. Interestingly, ZMYND8 expression was directly controlled by NRF2 in mammospheres. Collectively, these findings uncover a positive feedback loop that amplifies the antioxidant defense mechanism sustaining BCSC survival and stemness.

Authors

Maowu Luo, Lei Bao, Yuanyuan Xue, Ming Zhu, Ashwani Kumar, Chao Xing, Jennifer E. Wang, Yingfei Wang, Weibo Luo

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Figure 8

ZMYND8 increases NRF2 protein stability through KEAP1 silencing.

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ZMYND8 increases NRF2 protein stability through KEAP1 silencing.
(A) Ana...
(A) Analysis of ZMYND8, KEAP1, and NRF2 protein levels in MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO rescued with WT ZMYND8, K1007/1034R, or Y247A/N248A monolayers and mammospheres (n = 3). (B) Analysis of ZMYND8, KEAP1, and NRF2 protein levels in MCF-7-SC, ZMYND8 KO1/2, and ZMYND8 KO1/2 rescued with WT ZMYND8 monolayers and mammospheres (n = 3). (C) Analysis of NRF2 and ZMYND8 protein levels in MDA-MB-231-SC and ZMYND8 KO cells treated with DMSO (–) or MG132 (+, 10 μM for 2 hrs and 2.5 μM for an additional 22 hrs). n = 3. (D) Analysis of NRF2 and ZMYND8 protein levels in MCF-7-SC and ZMYND8 KO1/2 cells treated with DMSO (-) or MG132 (+). n = 3. (E and G) Analysis of NFE2L2 (E) and KEAP1 (G) mRNAs in MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO rescued with WT ZMYND8, K1007/1034R, or Y247A/N248A mammospheres (n = 3). (F) Analysis of NFE2L2 mRNA in MCF-7-SC and ZMYND8 KO1/2 mammospheres (n = 3). (H) Analysis of KEAP1 mRNA in MCF-7-SC, ZMYND8 KO1/2, and ZMYND8 KO1/2 rescued with WT ZMYND8 mammospheres (n = 3). Data represent mean ± SEM. P value was determined by using 1-way ANOVA corrected with Tukey’s test (E, G, and H) or Dunnett’s test (F). **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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