PMID- 38488001
OWN - NLM
STAT- MEDLINE
DCOM- 20240318
LR  - 20240319
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 134
IP  - 6
DP  - 2024 Jan 23
TI  - ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis 
      through activation of NRF2.
LID - 10.1172/JCI171166 [doi]
LID - e171166
AB  - 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.
FAU - Luo, Maowu
AU  - Luo M
AD  - Department of Pathology.
FAU - Bao, Lei
AU  - Bao L
AD  - Department of Pathology.
FAU - Xue, Yuanyuan
AU  - Xue Y
AD  - Children's Medical Center Research Institute.
FAU - Zhu, Ming
AU  - Zhu M
AD  - Department of Pathology.
FAU - Kumar, Ashwani
AU  - Kumar A
AD  - Eugene McDermott Center for Human Growth and Development.
FAU - Xing, Chao
AU  - Xing C
AD  - Eugene McDermott Center for Human Growth and Development.
AD  - Lyda Hill Department of Bioinformatics.
FAU - Wang, Jennifer E
AU  - Wang JE
AD  - Department of Pathology.
FAU - Wang, Yingfei
AU  - Wang Y
AD  - Department of Pathology.
AD  - Department of Neurology.
AD  - Peter O'Donnell Jr. Brain Institute.
AD  - Cecil H. and Ida Green Center for Reproductive Biology Sciences, and.
FAU - Luo, Weibo
AU  - Luo W
AD  - Department of Pathology.
AD  - Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA.
LA  - eng
GR  - R01 CA222393/CA/NCI NIH HHS/United States
GR  - R35 GM124693/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20240123
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Antioxidants)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Zmynd8 protein, rat)
RN  - 0 (Trans-Activators)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Antioxidants
MH  - *Ferroptosis/genetics
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - Neoplasms/metabolism
MH  - *Neoplastic Stem Cells/metabolism
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - *Trans-Activators/metabolism
MH  - *Breast Neoplasms/metabolism/pathology
PMC - PMC10940091
OTO - NOTNLM
OT  - Cell stress
OT  - Epigenetics
OT  - Stem cells
OT  - Transcription
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2024/03/15 12:46
MHDA- 2024/03/18 06:44
PMCR- 2024/01/23
CRDT- 2024/03/15 06:03
PHST- 2023/04/03 00:00 [received]
PHST- 2024/01/17 00:00 [accepted]
PHST- 2024/03/18 06:44 [medline]
PHST- 2024/03/15 12:46 [pubmed]
PHST- 2024/03/15 06:03 [entrez]
PHST- 2024/01/23 00:00 [pmc-release]
AID - 171166 [pii]
AID - 10.1172/JCI171166 [doi]
PST - epublish
SO  - J Clin Invest. 2024 Jan 23;134(6):e171166. doi: 10.1172/JCI171166.