An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling

Blocking genotoxic stress-induced NF-kappa B activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-kappa B pathway, the genotoxic agents-induced nuclear-to-cytoplasmic NF-kappa B pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-kappa B via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-kappa B activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-kappa B and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-node-metastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-kappa B pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-kappa B activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer. Significance: In response to genotoxic stress, TRIM37 activates NF-kappa B signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. (C) 2018 AACR.