Tet methylcytosine dioxygenase 2(TET2)deficiency elicits EGFR-TKI(tyrosine kinase inhibitors)resistance in non-small cell lung cancer

Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7^(FBXW11) and degraded in EGFR-TKI resistant NSCLC ells.Genetic perturbationof TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7^(FBXW11),Loss of TET2 resulted in the upregulation of TNF/NF-kB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-kB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.

Engineering a Circular Riboregulator in Escherichia coli

RNAs of different shapes and sizes,natural or synthetic,can regulate gene expression in prokaryotes and eukaryotes.Circular RNAs have recently appeared to be more widespread than previously thought,but their role in prokaryotes remains elusive.Here,by inserting a riboregulatory sequence within a group I permuted intron-exon ribozyme,we created a small noncoding RNA that self-splices to produce a circular riboregulator in Escherichia coli.We showed that the resulting riboregulator can trans-activate gene expression by interacting with a cis-repressed messenger RNA.We characterized the system with a fluorescent reporter and with an antibiotic resistance marker,and we modeled this novel posttranscriptional mechanism.This first reported example of a circular RNA regulating gene expression in E.coli adds to an increasing repertoire of RNA synthetic biology parts,and it highlights that topological molecules can play a role in the case of prokaryotic regulation.