Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Tumor Tissue Samples
2.2. QuantiGene Plex DNA Assay
2.3. Immunohistochemistry
2.4. Cell Lines and Cell Culture
2.5. EZH2 Gain Analysis
2.6. Cell Transient Transfections
2.7. Construction of Lentivirus and Stable Cell Lines
hEZH2 shRNA-1 target sequence | CAGGATGGTACTTTCATTGAA |
hEZH2 shRNA-2 target sequence | GTGCAGCTTTCTGTTCAACTT |
negative control sequence | TTCTCCGAACGTGTCACGT |
2.8. RNA Extraction and qRT-PCR
EZH2 forward primers | GACGGCTTCCCAATAACAGTAG |
EZH2 reverse primers | TTTGACACCGAGAATTTGCTTC |
SLC7A11 forward primers | TGTGTGGGGTCCTGTCACTA |
SLC7A11 reverse primers | CAGTAGCTGCAGGGCGTATT |
GAPDH forward primers | CCAGAACATCATCCCTGCCTCT |
GAPDH reverse primers | CCTGCTTCACCACCTTCTTGAT |
2.9. Western Blot
2.10. Cell Viability Assay
2.11. Immunofluorescence
2.12. RNA-Seq
2.13. Reactive Oxygen Species (ROS) Detection
2.14. MDA Measurements
2.15. GSH Assay
2.16. TEM
2.17. ChIP-Seq
SLC7A11-intron Forward | GAACCTGACCCTGGGAGAAAAC |
SLC7A11-intron Reverse | CTGAAGCTGTGATTTAAGGACTGG |
SLC7A11-promoter Forward | GCAAACCTGGAGAATTTGCATCA |
SLC7A11-promoter Reverse | CTTGTATTTAAGCGCCTGCCT |
KLF14-promoter-1 Forward | AACTTTCTGGGACTCCGC |
KLF14-promoter-1 Reverse | CCGGCTAAGTCATGTTTA |
KLF14-promoter-2 Forward | TGCAACTTGACAAACTAATGCT |
KLF14-promoter-2 Reverse | AAGGACATATCCTCTCTTTGTTCA |
2.18. Dual-Luciferase Reporter Assay
KLF14 binding site | AAGTTGGTGTGACA |
2.19. CDX Model and Treatment
2.20. PDX Model and Treatment
2.21. Statistical Analyses
3. Results
3.1. Copy Number Amplification of EZH2 Correlates with Poor MM Prognosis
3.2. EZH2 Is Required for MM Proliferation In Vitro and In Vivo
3.3. EZH2 Depletion Sensitizes MM Cells to Ferroptosis by Downregulation of SLC7A11
3.4. EZH2 Promotes SLC7A11 Expression by Repressing KLF14
3.5. Combination EZH2 Inhibitor and Ferroptosis Inducer Treatment Suppresses Tumorigenesis of MM
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Melanoma Subtypes | Number of Cases | Number of Cases with EZH2 Gain (%) |
---|---|---|
Acral melanoma | 252 | 58 (23.0) |
Mucosal melanoma | 148 | 64 (43.2) |
Cutaneous melanoma | 147 | 42 (28.6) |
Total | 547 | 164 (30.0) |
p value | <0.001 |
EZH2 Genotype | |||
---|---|---|---|
Clinicopathologic Feature | Gain | No Gain | p Value |
Age (year) | 55.1 ± 10.8 | 55.3 ± 10.7 | 0.953 |
Gender N (%) | 0.173 | ||
Man | 29 (45.3) | 28 (33.3) | |
Female | 35 (54.7) | 56 (66.7) | |
Ulceration N (%) | 0.694 | ||
Yes | 34 (69.4) | 45 (65.2) | |
No | 15 (30.6) | 24 (34.8) | |
Primary site | 0.615 | ||
Head and Neck | 25 (39.1) | 37 (44.0) | |
non-Head and Neck | 39 (60.9) | 47 (56.0) | |
TNM stage N (%) | 0.010 | ||
I II | 16 (25.0) | 39 (46.4) | |
III IV | 48 (75.0) | 45 (53.6) | |
Mutations N (%) | |||
NRAS | 0.240 | ||
Yes | 5 (7.8) | 2 (2.4) | |
No | 59 (92.2) | 82 (97.6) | |
BRAF | 1.000 | ||
Yes | 6 (9.4) | 7 (8.3) | |
No | 58 (90.6) | 77 (91.7) | |
CKIT | 0.473 | ||
Yes | 2 (3.1) | 5 (6.0) | |
No | 62 (96.9) | 79 (94.0) |
Variable | OS | |||||
---|---|---|---|---|---|---|
Univariate | Multivariate | |||||
HR | 95% CI | p Value | HR | 95% CI | p Value | |
Age (>60 years/≤60 years) | 0.83 | 0.54–1.28 | 0.40 | |||
Gender (female/male) | 0.75 | 0.50–1.14 | 0.179 | |||
Primary site (Head and Neck/non-Head and Neck) | 1.49 | 0.83–2.70 | 0.18 | |||
Ulceration (yes/no) | 1.21 | 0.74–1.99 | 0.442 | |||
TNM stage (I + II/III + IV) | 1.39 | 0.90–2.14 | 0.136 | |||
BRAF mutation (yes/no) | 0.93 | 0.45–1.92 | 0.84 | |||
NRAS mutation (yes/no) | 1.17 | 0.48–2.89 | 0.729 | |||
CKIT mutation (yes/no) | 0.92 | 0.34–2.52 | 0.875 | |||
EZH2 gain (yes/no) | 1.65 | 1.10–2.48 | 0.017 | 1.61 | 1.02–2.56 | 0.041 |
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Du, H.; Hou, L.; Yu, H.; Zhang, F.; Tong, K.; Wu, X.; Zhang, Z.; Liu, K.; Miao, X.; Guo, W.; et al. Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway. Cancers 2024, 16, 3660. https://doi.org/10.3390/cancers16213660
Du H, Hou L, Yu H, Zhang F, Tong K, Wu X, Zhang Z, Liu K, Miao X, Guo W, et al. Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway. Cancers. 2024; 16(21):3660. https://doi.org/10.3390/cancers16213660
Chicago/Turabian StyleDu, Haizhen, Lijie Hou, Huan Yu, Fenghao Zhang, Ke Tong, Xiaowen Wu, Ziyi Zhang, Kaiping Liu, Xiangguang Miao, Wenhui Guo, and et al. 2024. "Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway" Cancers 16, no. 21: 3660. https://doi.org/10.3390/cancers16213660
APA StyleDu, H., Hou, L., Yu, H., Zhang, F., Tong, K., Wu, X., Zhang, Z., Liu, K., Miao, X., Guo, W., Guo, J., & Kong, Y. (2024). Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway. Cancers, 16(21), 3660. https://doi.org/10.3390/cancers16213660