KDM1A, a potent and selective target, for the treatment of DNMT3A-deficient non-small cell lung cancer.

BACKGROUND: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies. METHODS: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction. RESULTS: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level. CONCLUSION: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.

Simplified equations of the compliant matrix for right elliptical flexure hinges.

The simplified compliance matrix for right elliptical hinges is presented in this paper by nonlinear curve fitting on the basis of the equations derived by Chen et al. [Rev. Sci. Instrum. 79, 095103 (2008)]. The equations of the rotation stiffness are then confirmed by comparison with results from finite element analysis and experimental measurements. Percentage errors between theoretical predictions and results from both the finite element analysis and experimental testing are within 5% for a range of geometries with the ratio s (b/t) between 1 and 14. The geometric parameter optimization for the purposes of maximizing the rotation stiffness for one universal hinge is utilized to illustrate the application of the simplified equations. The theoretical predictions are in good agreement with both the result of simulation and experiment for the universal hinge: the error between them is within 6.5%.