Functional relationship of SNP (Ala490Thr) of an epigenetic gene EZH2 results in the progression and poor survival of ER+/tamoxifen treated breast cancer patients
2021
EZH2 is a classic histone methyltransferase that causes the trimethylation of H3K27 and consequently suppresses the cancer preventive genes. The role of elevated levels of EZH2 expression in breast cancer aggressiveness and poor prognosis is very well established. The present study focusses on the insight of the clinically important SNPs of EZH2 gene in determining the structure–function relationship towards breast cancer susceptibility. For this purpose the EZH2 SNPs (rs41277434A>C and rs201135441C>T (A490T)) were computationally explored and further the prediction outcomes were validated by performing population-based association and pharmacogenetic study in north Indian region of Punjab. The results of the present analysis provided the novel insight of rs201135441C>T (A490T) mutation, that A>T change i.e. nonpolar amino acid to polar amino acid stabilizes the enzyme-substrate (EZH2-Histone) complex which in turn promotes trimethylation over histone 3 (H3) at lysine residue 27 (H3K27me3) and this might be leading to the methylation of the promoter region of various cancer preventive genes, hence may increase the risk of breast cancer susceptibility. Further the association based study of SNP rs201135441C>T (A490T) support the in silico outcomes by revealing that the T mutant allele of rs201135441 has significantly increased the risk of breast cancer susceptibility and also reduce the overall survival and progression free survival of ER+/tamoxifen treated breast cancer patients and triple negative breast cancer (TNBC) patients, respectively. To the best of our knowledge, this is the first study on EZH2 polymorphism with breast cancer. In conclusion, these findings suggest that these variations in the EZH2 gene may have strong clinical significance as they can be targeted for prognosis, prevention and in drug development.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
65
References
1
Citations
NaN
KQI