The E3 Ligase TRIM25 Impairs Apoptotic Cell Death in Colon Carcinoma Cells via Destabilization of Caspase-7 mRNA: A Possible Role of hnRNPH1

Cells. 2023 Jan 3;12(1):201. doi: 10.3390/cells12010201.


Therapy resistance is still a major reason for treatment failure in colorectal cancer (CRC). Previously, we identified the E3 ubiquitin ligase TRIM25 as a novel suppressor of caspase-2 translation which contributes to the apoptosis resistance of CRC cells towards chemotherapeutic drugs. Here, we report the executioner caspase-7 as being a further target of TRIM25. The results from the gain- and loss-of-function approaches and the actinomycin D experiments indicate that TRIM25 attenuates caspase-7 expression mainly through a decrease in mRNA stability. The data from the RNA pulldown assays with immunoprecipitated TRIM25 truncations indicate a direct TRIM25 binding to caspase-7 mRNA, which is mediated by the PRY/SPRY domain, which is also known to be highly relevant for protein-protein interactions. By employing TRIM25 immunoprecipitation, we identified the heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) as a novel TRIM25 binding protein with a functional impact on caspase-7 mRNA stability. Notably, the interaction of both proteins was highly sensitive to RNase A treatment and again depended on the PRY/SPRY domain, thus indicating an indirect interaction of both proteins which is achieved through a common RNA binding. Ubiquitin affinity chromatography showed that both proteins are targets of ubiquitin modification. Functionally, the ectopic expression of caspase-7 in CRC cells caused an increase in poly ADP-ribose polymerase (PARP) cleavage concomitant with a significant increase in apoptosis. Collectively, the negative regulation of caspase-7 by TRIM25, which is possibly executed by hnRNPH1, implies a novel survival mechanism underlying the chemotherapeutic drug resistance of CRC cells. The targeting of TRIM25 could therefore offer a promising strategy for the reduction in therapy resistance in CRC patients.

Keywords: RNA-binding proteins; TRIM25; apoptosis; caspase-7; colon carcinoma cells; hnRNPH1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Carcinoma*
  • Caspase 7
  • Cell Line, Tumor
  • Colonic Neoplasms* / genetics
  • Humans
  • RNA
  • RNA, Messenger / genetics
  • Transcription Factors / genetics
  • Tripartite Motif Proteins / genetics
  • Ubiquitin
  • Ubiquitin-Protein Ligases / metabolism


  • RNA, Messenger
  • Caspase 7
  • Ubiquitin-Protein Ligases
  • RNA
  • Ubiquitin
  • TRIM25 protein, human
  • Tripartite Motif Proteins
  • Transcription Factors

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (EB 257/6-2; FuGG Project-ID: 403765277). U.N. was financially supported by grants from SFB 1039.