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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Research Article

ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2

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 2

ZMYND8 promotes maintenance of ALDHhi BCSCs through reducing ROS.

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ZMYND8 promotes maintenance of ALDHhi BCSCs through reducing ROS. (A–C) ...
(A–C) Formation of MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO mammospheres treated with vehicle, NAC, or GSH-EE. Representative mammosphere images (A). Quantification of primary mammosphere numbers (B) and mammosphere expansion and self-renewal (C, n = 3). (D and E) Formation of MCF-7-SC, ZMYND8 KO1, and ZMYND8 KO2 mammospheres treated with DMSO, NAC, or GSH-EE. Representative mammosphere images (D). Quantification of primary mammosphere numbers (E, n = 3). (F) Quantification of ALDHhi BCSCs in MDA-MB-231-SC and ZMYND8 KO cells treated with or without NAC (n = 3). (G) Limiting dilution assay of MDA-MB-231-SC and ZMYND8 KO cells in NSG mice (n = 5). Mice implanted with ZMYND8 KO cells were fed with regular or NAC water. Data represent mean ± SEM. P values were determined by using 1-way ANOVA corrected with Tukey’s test (B, C, and F) or 2-way ANOVA corrected with Tukey’s test (E), and κ2 test (G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 200 μm.