Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Apr;10(4):637-643.
doi: 10.1002/2211-5463.12823. Epub 2020 Mar 18.

Histone demethylase KDM3B protects against ferroptosis by upregulating SLC7A11

Yishu Wang  1 , Yao Zhao  1 , Haihua Wang  1 , Chengliang Zhang  2 , Meiqi Wang  2 , Yong Yang  1 , Xin Xu  1   2 , Zhenbo Hu  1
Affiliations

Histone demethylase KDM3B protects against ferroptosis by upregulating SLC7A11

Yishu Wang et al. FEBS Open Bio. 2020 Apr.

Abstract

Ferroptosis is a type of adaptive cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Though multiple genes (including SLC7A11 and GPX4) have been demonstrated to play key roles in ferroptosis, little is known about the epigenetic regulation of this process. Here, we report that KDM3B, a histone H3 lysine 9 demethylase, can protect against ferroptosis induced by Erastin, an inhibitor of SLC7A11. KDM3B overexpression in HT-1080 cells results in decreased histone H3 lysine 9 methylation. Furthermore, KDM3B upregulates the expression of SLC7A11 through cooperation with the transcription factor ATF4. In summary, we identify here KDM3B as a potential epigenetic regulator of ferroptosis.

Keywords: ATF4; KDM3B; SLC7A11; ferroptosis; histone; histone demethylase.

PubMed Disclaimer

Conflict of interest statement

All authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
The effect of KDM3B overexpression on the Erastin‐induced ferroptosis. (A) The effect of KDM3B in HT‐1080 cells on the ferroptosis induced by Erastin (5 μm) and RSL3 (2.5 μm). KDM3B stably overexpressed HT‐1080 was constructed as described in the materials and methods. Parental and KDM3B over cells were plated in 96‐well plates at a concentration of 1500 cells per well and incubated with indicated compounds 24 h after plating. Three days later, cells were collected for proliferation detection. (B) The effect of JMJD1C in 293 cells on the ferroptosis induced by Erastin (5 μm) and RSL3 (2.5 μm). JMJD1C stably overexpressed 293 was constructed as described in the materials and methods. Parental and JMJD1C over cells were plated in 96‐well plates at a concentration of 1500 cells per well and incubated with indicated compounds 24 h after plating. Three days later, cells were collected for proliferation detection. (C) The effect of KDM3B stable overexpression on the H3K9 monomethylation and dimethylation of HT‐1080 cells. Parental and KDM3B over HT‐1080 cells were collected and lysed for Western blot detection. H3 was used as endogenous control. (D) The effect of JMJD1C stable overexpression on the H3K9 monomethylation and dimethylation of 293 cells. Parental and JMJD1C over HT‐1080 cells were collected and lysed for Western blot detection. H3 was used as endogenous control. (E) The effect of KDM3B inhibitor JDI‐16 on Erastin‐induced repression of cell proliferation of THP‐1 cells. THP‐1 cells were plated in 96‐well round‐bottom plates at a concentration of 4000 cells per well and incubated with indicated compounds (Erastin, 5 μm, JDI‐16, 12.5 μm) 24 h after plating. Four days later, cells were collected for proliferation detection. For (A, B, E), three independent experiments were performed, quantitative results are reported as mean ± SD, the statistical analysis was performed using Student's t‐test, and P value smaller than 0.05 (represented by *) was regarded as statistically significant.
Fig. 2
Fig. 2
The transcriptional regulation of SLC7A11 by KDM3B. (A–F) The mRNA levels of indicated genes affected by KDM3B overexpression. Parental and KDM3B overexpressed HT‐1080 cells were collected for RNA extraction and qPCR. GAPDH was used as an endogenous control. (G) The effect of enforced ATF4, p53, KDM3B, and the combination on the SLC7A11 promoter activities. The SLC7A11 promoter reporter along with ATF4, p53, and KDM3B plasmids was transfected into HT‐1080 cells with pRL‐TK as an endogenous control. (H) The effect of enforced ATF4 and KDM3B siRNA on the SLC7A11 promoter activities. The SLC7A11 promoter reporter along with ATF4 and KDM3B siRNA was transfected into HT‐1080 cells with pRL‐TK as an endogenous control. For (A–H), three independent experiments were performed, quantitative results are reported as mean ± SD, the statistical analysis was performed using Student's t‐test, and P value smaller than 0.05 (represented by *) was regarded as statistically significant.
Fig. 3
Fig. 3
The effect of JMJD1C overexpression on SLC7A11 mRNA. (A) JMJD1C and (B) SLC7A11 mRNA levels after JMJD1C transfection into 293T cells. 293T cells were transfected with JMJD1C plasmids as described in materials and methods and collected for RNA extraction and qPCR. GAPDH was used as an endogenous control. Three independent experiments were performed. Quantitative results are reported as mean ± SD. The statistical analysis was performed using Student's t‐test. P value smaller than 0.05 (represented by *) was regarded as statistically significant.
Fig. 4
Fig. 4
Schematic representation of the proposed model that characterizes KDM3B's role in Erastin‐induced ferroptosis. Class I FIN (ferroptosis inducer) Erastin and class II FIN RSL3 induce ferroptosis dependent on SLC7A11 and GPX4, respectively. KDM3B transcriptionally upregulates SLC7A11, probably through ATF4 and p53, to confer ferroptosis resistance. KDM3B also represses VDAC3 and CARS. KDM3B inhibitor JDI‐16 could resensitize cells to Erastin‐induced proliferation repression.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285. - PMC - PubMed
    1. Yang WS, Sriramaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331. - PMC - PubMed
    1. Jiang L, Kon N, Li T, Wang S‐J, Su T, Hibshoosh H, Baer R and Gu W (2015) Ferroptosis as a p53‐mediated activity during tumour suppression. Nature 520, 57–62. - PMC - PubMed
    1. Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, Lai W, Liu Y, Wang X, Xiao D et al (2017) EGLN1/c‐Myc induced lymphoid‐specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics 7, 3293–3305. - PMC - PubMed
    1. Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, Sirohi K, Li X, Wei Y, Lee H et al (2018) BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol 20, 1181–1192. - PMC - PubMed

Publication types

MeSH terms