USP14 and UCHL5 synergistically deubiquitinate PKCα and translocate NF-κB to promote the progression of anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC), an exceptionally aggressive and rare subtype of thyroid cancer, accounts for 1-2% of all thyroid cancers yet carries a high mortality rate, with a median survival time of less than one year. Despite significant advancements in in the field of thyroid cancer research, effective therapeutic options for ATC remain notably limited. Recently, targeting deubiquitinating enzymes (DUBs) has emerged as a promising strategy in cancer therapy. In this study, we investigated the roles of two DUBs, USP14 and UCHL5, in the progression of ATC. Our findings revealed that both USP14 and UCHL5 were upregulated at both mRNA and protein levels in ATC. Individually silencing USP14 or UCHL5 significantly inhibited the malignant characteristics of ATC, while the simultaneous knockdown of both DUBs proved to be even more efficacious. Furthermore, b-AP15, a dual-targeting inhibitor acting on USP14 and UCHL5, effectively suppressed tumor growth in nude mice. Mechanistically, USP14 and UCHL5 cooperate to stabilize PKCα by concurrently removing K48-linked ubiquitination chains from PKCα, thereby facilitating the nuclear translocation of transcription factor NF-κB and activating the expression of pro-oncogenic and anti-apoptotic genes, such as C-MYC and BCL-XL. These findings suggest that targeting the USP14/UCHL5-PKCα-NF-κB axis may represent a novel therapeutic approach for ATC, offering promising prospects for the development of innovative treatment strategies against this highly lethal disease.