DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer

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