DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.

Objective To compare the efficacy of inhaled Iloprost and nitric oxide( NO)in infants with moderate or severe pulmonary hypertension(PH)after congenital heart disease surgery. Methods This was a prospec-tive randomized study in Children's Hospital of Fudan University from January 2011 to January 2014,including 40 in-fants who suffered from moderate to severe PH after heart surgery. Their ages ranged from 1 to 24 months. Their weight ranged from 3. 2 to 11. 0 kg. They were randomly allocated to inhale NO( NO group,n = 20)or Iloprost( Iloprost group,n = 20). Iloprost group was given Iloprost with 50 ng/(kg·min)for 10 min and then combined with NO 20 × 10 - 6 for 10 min;NO group was first given 20 × 10 - 6 of NO for 10 min,then combined with Iloprost 50 ng/(kg·min) for 10 min. Heart rate,systolic blood pressure,pulmonary artery pressure(PAP)and central venous pressure were recor-ded continuously. At the same time,the concentration of nitrogen dioxide and methemoglobin after inhaling NO was de-tected. Results Inhaled Iloprost and NO caused significant reduction in PAP(t = 4. 670,P = 0. 009;t = 3. 762,P =0. 004)and pulmonary - to - systemic pressure ratio(Pp/ Ps)(t = 16. 974,P = 0. 000;t = 9. 682,P = 0. 000)but signifi-cant increase in oxygen index separately. The combination had no additional effect compared with single application. In term of the reduction of PAP,there was no significant difference between inhaled Iloprost and NO(F = 2. 742,P =0. 129). The levels of nitrogen dioxide and methemoglobin were not above the normal limits. Conclusions Moderate to severe PH after cardiac surgery was significantly reduced by inhaled NO and Iloprost. They had similar effects. However, the combination of both vasodilators failed to prove more potent than either substance alone. Compared with the potential toxicity of NO,the individual differences and the complex transmission,Iloprost may be more reasonable and feasible for the postoperative treatment of PH.

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.