An Essential Role of Alternative Splicing of c-myc Suppressor FUSE-Binding Protein–Interacting Repressor in Carcinogenesis

Kazuyuki Matsushita,Takeshi Tomonaga,Hisahiro Matsubara,Hideaki Shimada,Kenichi Harigaya,Ayumi Shioya,Fumio Nomura,Daniel Libutti,Takenori Ochiai,David Levens,Morihiro Higashi

doi:10.1158/0008-5472.can-04-4459

Abstract

Elevated expression of c-myc has been detected in a broad range of human cancers, indicating a key role for this oncogene in tumor development. Recently, an interaction between FUSE-binding protein-interacting repressor (FIR) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and might be important for suppressing tumor formation. In this study, we showed that enforced expression of FIR induced apoptosis. Deletion of the NH(2)-terminal repression domain of FIR rescued the cells from apoptosis as did coexpression of c-Myc with FIR; thus, repression of Myc mediates FIR-driven apoptosis. Surprisingly, a splicing variant of FIR unable to repress c-myc or to drive apoptosis was frequently discovered in human primary colorectal cancers but not in the adjacent normal tissues. Coexpression of this splicing variant with repressor-competent FIR, either in HeLa cells or in the colon cancer cell line SW480, not only abrogated c-Myc suppression but also inhibited apoptosis. These results strongly suggest the expression of this splicing variant promotes tumor development by disabling FIR repression and sustaining high levels of c-Myc and opposing apoptosis in colorectal cancer.

Highlights

Introduction cMyc plays a critical role in cell proliferation and tumorigenesis
This study showed that far upstream element (FUSE)-binding protein–interacting repressor (FIR) strongly repressed endogenous c-myc transcription and induced apoptosis
The alternative splicing of FIR may contribute to tumor progression by enabling higher levels of c-myc expression and greater resistance to apoptosis in tumors than in normal cell

Summary

Introduction

The c-myc proto-oncogene is activated in a variety of tumors, and its ectopic expression induces transformation. The recent genetic construction of mice in which the expression of c-myc can be switched on or off in vivo has emphasized the significance of c-Myc expression for tumorigenesis. C-myc activation was shown to be required for skin epidermal and pancreatic h-cell tumor maintenance in c-MYC-ERTAM transgenic mice [2, 3]. These observations have provided encouragement for the future development of cancer therapies based on targeting individual oncogenes, such as c-myc.

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Conclusion