OTU deubiquitinase 7B facilitates the hyperthermia-induced inhibition of lung cancer progression through enhancing Smac-mediated mitochondrial dysfunction.

Hyperthermia, as an adjuvant therapy, has shown promising anti-tumor effects. Ovarian tumor domain-containing 7B (OTUD7B) is a deubiquitinating enzyme that is frequently found in a variety of cancers. The aim of this study is to investigate the role of OTUD7B in lung cancer hyperthermia and the underlying mechanism. A549 and CALU-3 cells were respectively exposed to 42 or 44°C for the indicated times (0, 1, 3, or 6 h) followed by incubation at 37°C for 24 h. We found a temperature- and time-dependent decrease in cell viability and an increase in apoptosis levels. Compared with 0 h, heat treatment for 3 h inhibited the proliferation and invasion of A549 cells, reduced the expression levels of mitochondrial membrane potential, IAP family members (cIAP-1 and XIAP) proteins and ubiquitination of Smac, and increased Smac protein expression. Treatment with 10 μM Smac mimic BV6 further enhanced the anti-tumor effect of hyperthermia. Next, co-IP validation showed that OTUD7B interacted with Smac and stabilized Smac through deubiquitination. OTUD7B overexpression induced damage in A549 and CALU-3 cells, while silencing OTUD7B caused opposite effects. Overexpressing OTUD7B enhanced the anti-cancer effect of hyperthermia, while si-OTUD7B reversed the anti-cancer effect of hyperthermia, which was verified in the xenograft tumor model in nude mice. Taken together, OTUD7B may serve as a potential anticancer factor with potential clinical efficacy in the thermotherapeutic treatment of lung cancer.
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