The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor

Abstract

Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression.

RETRACTED ARTICLE: The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA

“…Ubiquitination is a key determinant of protein degradation. Here, we reported that LINC00623 acts as a scaffold supporting the interaction of NAT10 with USP39, a member of a deubiquitinase family of proteins that has been reported to be an oncogene in several cancers [ 43 , 66 – 69 ]. A site mutation (C306) in USP39 abrogated its deubiquitinase activity and led to the degradation of NAT10 in PDAC cells.…”

USP39 stabilizes β-catenin by deubiquitination and suppressing E3 ligase TRIM26 pre-mRNA maturation to promote HCC progression

“…Loss of USP39 leads to aberrant RB1 mRNA splicing, which may lead to increased expression of its target E2F4, a key regulator known to have oncogenic activity when overexpressed [ 44 ]. USP39 regulates mTORC2 activity by selectively enhancing the splicing and maturation of Rictor mRNA to promote ESCC [ 45 ].…”

Chloride intracellular channel 1 promotes esophageal squamous cell carcinoma proliferation via mTOR signalling

“…CLIC1 expression was graded semi-quantitatively, combining the staining intensity with percentage of positive tumor cells. Immunoreactivity was blindly evaluated by two professional pathologists to according to immunoreactivity score (IRS) system as previously described [29] . For CLIC1 analysis, we combined weak positive and negative staining cases as low expression, and moderate and strong positive staining as high expression.…”

“…However, presently there are few related studies detailing whether the PI3K/Akt signaling pathway promotes the progression of ESCC and consequently further exploration is required. mTOR is a serine/threonine protein kinase in the PI3K related kinase family, and is one of the downstream molecules of the PI3K/Akt signaling pathway [29] . mTOR can form two protein complexes, namely mTOR complex 1 (mTORC1) including mTOR, Raptor and mLST8, and mTOR complex 2 (mTORC2) including mTOR, Rictor and mLST8 [30] , [31] , [32] .…”