Tripartite motif protein 25 is associated with epirubicin resistance in hepatocellular carcinoma cells via regulating PTEN/AKT pathway

Abstract

Tripartite motif protein 25 (TRIM25) expression was altered in various human cancers. Herein, we found that the expression of TRIM25 was elevated in hepatocellular carcinoma (HCC) tissues and cell lines. Knockdown of TRIM25 increased the sensitivity of HCC HepG2 cells to epirubicin (EPI), as indicated by reduced cell viability, enhanced cell apoptosis, and downregulated P‐glycoprotein (P‐gp) and multiple drug‐resistance protein 1 (MRP1). Moreover, TRIM25 knockdown strengthened the effects of EPI on phosphatase and tensin homolog (PTEN) and phosphorylated (p)‐AKT. However, overexpression of TRIM25 exerted an opposite effect, weakening the sensitivity of Huh7 to EPI, and obviously increasing PTEN and reducing p‐AKT. Most important, all the changes induced by TRIM25 overexpression in Huh7 were reversed with additional treatment of LY294002 (an AKT pathway inhibitor). Notably, coimmunoprecipitation experiments confirmed the interaction between TRIM25 and PTEN. Knockdown of TRIM25 resulted in reduced ubiquitination of PTEN protein. Collectively, our data suggested that TRIM25 enhanced EPI resistance via modulating PTEN/AKT pathway, and targeting TRIM25 may enhance the sensitivity of HCC cells toward chemotherapy drugs.

The role of ubiquitination and deubiquitination in cancer metabolism

“…Upregulation of LINC00152 enhances NEDD4 mediated ubiquitination and degradation of PTEN in breast cancer [99]. E3 ligase WWP2, TRIM10, TRIM14, TRIM25, TRIM27, TRIM59 and XIAP can target PTEN for ubiquitination and degradation as well [100][101][102][103][104][105][106]. AKT activated MKRN1 E3 ligase also mediates ubiquitination and degradation of PTEN, thus positively regulating PI3K/AKT signaling axis [107].…”

TRIM proteins in hepatocellular carcinoma

“…Besides, TRIM25 strengthens sensitivity to epirubicin through promoting ubiquitin degradation of PTEN [ 32 ]. TRIM32 induces oxaliplatin resistance [ 35 ].…”

Small Nucleolar RNA and C/D Box 15B Regulate the TRIM25/P53 Complex to Promote the Development of Endometrial Cancer

“…The ring finger domain has ubiquitin ligase activity, and the coiled-coil region binds to RNA and regulates gene expression post-transcriptionally [ 20 ]. TRIM25 is overexpressed in multiple malignancies, including breast cancer [ 19 , 21 , 22 ], lung cancer [ 23 , 24 ], liver cancer [ 25 , 26 ], colorectal cancer [ 27 ], prostate cancer [ 28 ], and ovarian cancer [ 29 ]. We detected complementary pairing sequences between SNORD15B and TRIM25, and further verified their direct interaction through rRNA 2′-O-methyltransferase FBL in cells overexpressing SNORD15B.…”