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

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 3

ZMYND8 inhibits ferroptosis in ALDHhi BCSCs.

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ZMYND8 inhibits ferroptosis in ALDHhi BCSCs. (A) Death of ALDHhi BCSCs i...
(A) Death of ALDHhi BCSCs in MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO rescued with WT ZMYND8, K1007/1034R, or Y247A/N248A mammospheres (n = 4). (B and C) Formation of MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO mammospheres treated with vehicle, Ferrostatin-1, Z-VAD-FMK, or Olaparib. Representative mammosphere images (B). Quantification of mammosphere numbers (C, n = 3). (D) Quantification of ALDHhi BCSCs in MDA-MB-231-SC and ZMYND8 KO cells treated with or without Ferrostatin-1 (n = 3). (E and F) Formation of MDA-MB-231-SC, ZMYND8 KO, and ZMYND8 KO mammospheres treated with vehicle, Erastin, or Liproxstatin-1. Representative mammosphere images (E). Quantification of mammosphere numbers (F, n = 3). (G and H) Quantification of ALDHhi BCSCs in MDA-MB-231-SC and ZMYND8 KO cells treated with or without Liproxstatin-1 (G) or Erastin (H, n = 3). (I–K) Quantification of GSH/GSSG (I), Fe2+ (J), and lipid peroxidation (K) in MDA-MB-231-SC, ZMYND8 KO, ZMYND8 KO rescued with WT ZMYND8, K1007/1034R, or Y247A/N248A mammospheres (n = 3-4). Data represent mean ± SEM. P value was determined by using 1-way ANOVA corrected with Tukey’s test (A, D, I–K) or 2-way ANOVA corrected with Tukey’s test (C, F, G, and H). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 200 μm.