Abstract
Overexpression of alternative splicing of far upstream element binding protein 1 (FUBP1) interacting repressor (FIR; poly(U) binding splicing factor 60 [PUF60]) and cyclin E were detected in esophageal squamous cell carcinomas (ESCC). Accordingly, the expression of FBW7 was examined by which cyclin E is degraded as a substrate via the proteasome system. Expectedly, FBW7 expression was decreased significantly in ESCC. Conversely, c-myc gene transcriptional repressor FIR (alias PUF60; U2AF-related protein) and its alternative splicing variant form (FIRΔexon2) were overexpressed in ESCC. Further, anticancer drugs (cis-diaminedichloroplatinum/cisplatin [CDDP] or 5-fluorouracil [5-FU]) and knockdown of FIR by small interfering RNA (siRNA) increased cyclin E while knockdown of FIRΔexon2 by siRNA decreased cyclin E expression in ESCC cell lines (TE1, TE2, and T.Tn) or cervical SCC cells (HeLa cells). Especially, knockdown of SAP155 (SF3b1), a splicing factor required for proper alternative splicing of FIR pre-mRNA, decreased cyclin E. Therefore, disturbed alternative splicing of FIR generated FIR/FIRΔexon2 with cyclin E overexpression in esophageal cancers, indicating that SAP155 siRNA potentially rescued FBW7 function by reducing expression of FIR and/or FIRΔexon2. Remarkably, Three-dimensional structure analysis revealed the hypothetical inhibitory mechanism of FBW7 function by FIR/FIRΔexon2, a novel mechanism of cyclin E overexpression by FIR/FIRΔexon2-FBW7 interaction was discussed. Clinically, elevated FIR expression potentially is an indicator of the number of lymph metastases and anti-FIR/FIRΔexon2 antibodies in sera as cancer diagnosis, indicating chemical inhibitors of FIR/FIRΔexon2-FBW7 interaction could be potential candidate drugs for cancer therapy. In conclusion, elevated cyclin E expression was, in part, induced owing to potential FIR/FIRΔexon2–FBW7 interaction in ESCC.
Highlights
Unlike Western populations, esophageal cancer among Japanese populations consists predominately of squamous cell carcinoma (SCC)
This study proposed a novel mechanism that alternative splicing (AS) of FUBP1-interacting repressor (FIR) expression is strongly related to cyclin E overexpression by inhibiting the degron pocket of F-box and WD repeat domain-containing 7 (FBW7) which is pivotal for proliferation in esophageal squamous cell carcinomas (ESCC)
These results indicated that the function rather than the expression of FBW7 was obstructed directly or indirectly by reduced SAP155 expression
Summary
Unlike Western populations, esophageal cancer among Japanese populations consists predominately of squamous cell carcinoma (SCC). Revealing the dysregulated DNA damage response mechanism is required for understanding of ESCC carcinogenesis [1, 2]. Far upstream element binding protein 1 (FUBP1), a transcriptional activator of the c-myc gene, is activated in many cancers [7, 8]. FUBP1-interacting repressor (FIR) is a c-myc gene transcriptional repressor [9] and is a splicing variant of poly(U) binding splicing factor 60 (PUF60) [5]. FIR/PUF60 is a multifunctional protein through AS, engaging in c-myc gene transcriptional repression, [10] RNA splicing, [5] and DNA damage repair [4]. The expression of FBW7, FIR, and cyclin E in human excised ESCC was examined in association with clinical significance, lymph node metastasis, and prognosis or treatment response. A novel mechanism of cyclin E overexpression by possible FIRs-FBW7 interaction is discussed
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