ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression [ChIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1191431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31531100_1.fastq.gz | Fastqsanger.gz | |||
| SRR31531100_2.fastq.gz | Fastqsanger.gz | |||
| SRR31531101_1.fastq.gz | Fastqsanger.gz | |||
| SRR31531101_2.fastq.gz | Fastqsanger.gz | |||
| SRR31531102_1.fastq.gz | Fastqsanger.gz |
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Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
2025-01-30 | GSE282996 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
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Project description:ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression [RNA-Seq]
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Project description:The basic helix-loop-helix (bHLH) transcription factor ‘Atoh8’ is involved in the regulaton of several developmental processes and pathologies. It regulates organogenesis, reprogramming, stem cell fate determination, and cancer development. However, the mech anisms underlying these observations remain unclear. Unlike many tissue-specific bHLH factors, Atoh8 is ubiquitously expressed during development as well as in adult tissue. In this study, we explored whether Atoh8 modulates basic cellular functions, which may reveal a common mechanism that could explain the diverse observations reported in the literature. In the present study, our findings indicate that the loss of Atoh8 impairs autophagy. We observed differential expression of LC3B-II, TFEB, and accumulation of p62 in the absence or downregulation of Atoh8 in multiple cell lines. Moreover, mass spectrometric analysis of protein lysates from the tibialis anterior (TA) muscle in both wildtype and Atoh8 knockout mice revealed a significant downregulation of proteins associated with the initiation of autophagy (DEPTOR, PRAS40), autophagosome maturation (PDCD6IP, CHMP5), and autolysosomal degradation (NPC2, CTSB, CTSL). Additionally, the analysis indicated altered metabolism in the absence of Atoh8. Moreover, we determined that persistently elevated levels of reactive oxygen species (ROS) may be the primary factor contributing to the impairment of autophagy in the absence or downregulation of Atoh8.Overall, this study underscores that Atoh8 is a crucial regulator of autophagy, and its reduction or absence disrupts the autophagic process.
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Project description:While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress, which was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
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Project description:While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress, which was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
2023-04-03 | GSE226414 | GEO
Project description:While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress, which was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
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Project description:While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress, which was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
2023-04-03 | GSE226423 | GEO
Project description:While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress, which was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
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