Morgan EL, Toni T, Viswanathan R, Robbins Y, Yang X, Cheng H, Gunti S, Huynh A, Sowers AL, Mitchell JB, Allen CT, Chen Z, Van Waes C

TNF? is a key mediator of immune, chemotherapy and radiotherapy-induced cytotoxicity, but several cancers, including head and neck squamous cell carcinomas (HNSCC), display resistance to TNF? due to activation of the canonical NF?B pro-survival pathway. However, direct targeting of this pathway is associated with significant toxicity; thus, it is vital ...

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to identify novel mechanism(s) contributing to NF?B activation and TNF? resistance in cancer cells. Here, we demonstrate that the expression of proteasome-associated deubiquitinase USP14 is significantly increased in HNSCC and correlates with worse progression free survival in Human Papillomavirus (HPV)- HNSCC. Inhibition or depletion of USP14 inhibited the proliferation and survival of HNSCC cells. Further, USP14 inhibition reduced both basal and TNF?-inducible NF?B activity, NF?B-dependent gene expression and the nuclear translocation of the NF?B subunit RELA. Mechanistically, USP14 bound to both RELA and I?B? and reduced I?B? K48-ubiquitination leading to the degradation of I?B?, a critical inhibitor of the canonical NF?B pathway. Furthermore, we demonstrated that b-AP15, an inhibitor of USP14 and UCHL5, sensitized HNSCC cells to TNF?-mediated cell death, as well as radiation-induced cell death in vitro. Finally, b-AP15 delayed tumor growth and enhanced survival, both as a monotherapy and in combination with radiation, in HNSCC tumor xenograft models in vivo, which could be significantly attenuated by TNF? depletion. These data offer new insights into the activation of NF?B signaling in HNSCC and demonstrate that small molecule inhibitors targeting the ubiquitin pathway warrant further investigation as a novel therapeutic avenue to sensitize these cancers to TNF?- and radiation-induced cytotoxicity.

Date: May. 01, 2023

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