Ubiquitin‐specific peptidase 10 attenuates the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6

Abstract

PurposeUbiquitin‐specific peptidase 10 (USP10) has been found to have oncogenic activity in several human tumors. This study first revealed the exact function of USP10 on the progression of thyroid cancer (THCA) by researching its effect on the ferroptosis.MethodsUSP10 expression in THCA patients was analyzed by online data analysis and in 75 THCA cases was scrutinized by real‐time quantitative reverse transcription‐polymerase chain reaction and Western blot. Influence of USP10 on the viability, colony formation, migration and invasion of THCA cells was demonstrated by cell counting kit‐8, colony formation, wound healing and Transwell invasion assays. Effect of USP10 on the Erastin‐induced ferroptosis in THCA cells was evaluated by detecting the ferroptosis‐related indicators. Intrinsic mechanism of USP10, glutathione peroxidase 4 (GPX4) and sirtuin 6 (SIRT6) in regulating THCA progression was identified. In vivo xenograft experiment was implemented.ResultsUSP10 was abundantly expressed in THCA patients, linking to poor outcome. USP10 overexpression enhanced the viability, colony formation, migration and invasion of THCA cells. USP10 mitigated the Erastin‐induced ferroptosis in THCA cells, decreased the levels of iron, Fe2+, malondialdehyde, lipid reactive oxygen species, reduced mitochondrial superoxide level, and increased mitochondrial membrane potential. USP10 facilitated the expression of ferroptosis suppressor GPX4 by elevating SIRT6. Loss of USP10 repressed the in vivo growth of THCA cells.ConclusionUSP10 might attenuate the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6. It might be novel target for the treatment of THCA.

Ubiquitin-modifying enzymes in thyroid cancer：Mechanisms and functions

“…Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of cell death accompanied by massive lipid peroxidation-induced mitochondrial damage. In a recent study, DUB USP10 expression was increased in PTC, which promotes the expression of the ferroptosis inhibitor Glutathione Peroxidase 4 (GPX4) by elevating sirtuin 6 (SIRT6), thereby enhancing PTC proliferation, migration, and invasion [ 131 ].…”

Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements

“…The GPX4-targeting compound RSL3 can induce cell death in colorectal cancer cells, exhibiting characteristics consistent with ferroptosis. Conversely, the overexpression of GPX4 has been shown to mitigate cell death 51,85 . Additionally, SLC7A11 functions as a subunit of the cystine-glutamate reverse transport system, known as System x-c, and exhibits significantly elevated expression levels in various tumor tissues, indicating its close association with malignant tumors 41,52,86 .…”