USP47-Mediated Deubiquitination and Stabilization of TCEA3 Attenuates Pyroptosis and Apoptosis of Colorectal Cancer Cells Induced by Chemotherapeutic Doxorubicin

Abstract

The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.

Molecular mechanisms associated with the chemoprotective role of protocatechuic acid and its potential benefits in the amelioration of doxorubicin-induced cardiotoxicity: A review

“…Pyroptosis is the inflammatory form of programmed cell death (apoptosis), which occurs upon infection with intracellular pathogens. Although generally occurring as a result of the inflammatory response to microbes, pyroptosis has been identified as one of the major cell death forms associated with DIC [103] , [104] . By upregulating the expression of BH3-only protein Bcl-2/adenovirus E1B19-kDa-interacting protein 3 (Bnip3) in myocytes, it triggers the activation of caspase-3, cleavage of Gasdermin E (GSDME), membrane rupture, and pyroptosis in cardiomyocytes [105] , [106] .…”

Pyroptosis: A Developing Foreland of Ovarian Cancer Treatment

“…In a study focusing on nasopharyngeal carcinoma (NPC), it was discovered that caspase-1 inhibition and GSDMD knockout could induce a Taxol-resistant phenotype in vitro and in vivo and that autophagy could negatively regulate the canonical pathway of pyroptosis in NPC cells (127). Additionally, it was also found that the knockdown of USP47, a cysteine protease, could increase doxorubicin-induced pyroptosis in CRC while the ectopic expression of USP47 leads to doxorubicin resistance in CRC cells (128). Thus, we speculate the fact that patients taking particular drugs with dual effects experience drug resistance or tumor relapse might possibly result from the fine regulation of the intricate PCD pathway network.…”

Comprehensive analysis of pyroptotic gene prognostic signatures associated with tumor immune microenvironment and genomic mutation in breast cancer

“…In addition, aberrant ubiquitin regulation of inflammatory pathways can induce the onset and progression of cancers and autoinflammatory diseases, and thus targeting dysfunctional ubiquitination may be a promising treatment strategy ( 55 ). For instance, downregulation of deubiquitinating enzyme USP47 is associated with shorter disease-free survival of colorectal cancer (CRC) patients, and USP47-mediated deubiquitination of transcription elongation factor a3 can inhibit pyroptosis and apoptosis of CRC cells treated with chemotherapeutic doxorubicin, which may be a target for therapeutic intervention in CRC ( 59 ).…”