Overexpression of the Far Upstream Element Binding Protein 1 in Hepatocellular Carcinoma Is Required for Tumor Growth†

Abstract

We identified the far upstream element binding protein 1 (FBP1), an activator of transcription of the proto-oncogene c-myc, in a functional yeast survival screen for tumor-related antiapoptotic proteins and demonstrated strong overexpression of FBP1 in human hepato-cellular carcinoma (HCC). Knockdown of the protein in HCC cells resulted in increased sensitivity to apoptotic stimuli, reduced cell proliferation, and impaired tumor formation in a mouse xenograft transplantation model. Interestingly, analysis of gene regulation in these cells revealed that c-myc levels were not influenced by FBP1 in HCC cells. Instead, we identified the cell cycle inhibitor p21 as a direct target gene repressed by FBP1, and in addition, expression levels of the proapoptotic genes tumor necrosis factor α, tumor necrosis factor–related apoptosis-inducing ligand, Noxa, and Bik were elevated in the absence of FBP1. Conclusion Our data establish FBP1 as an important oncoprotein overexpressed in HCC that induces tumor propagation through direct or indirect repression of cell cycle inhibitors and proapoptotic target genes.

The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

“…We performed a functional yeast survival screen with a human breast carcinoma-derived cDNA library in order to identify novel anti-apoptotic proteins involved in tumorigenesis. 17,18 Among others, we isolated a cDNA clone coding for an N-terminal deletion mutant of the anti-apoptotic Aven protein. This clone, which efficiently suppressed yeast cell death induced by the proapoptotic C. elegans protein CED-4 (see Supplementary Figure 1), lacks the coding sequence for the N-terminal 179 aa (amino acid) of the protein (DN-Aven 180-362).…”

The Splicing Factor FUBP1 Is Required for the Efficient Splicing of Oncogene MDM2 Pre-mRNA

“…FUBP1 is single strand DNA and RNA-binding protein best known for its role as a transcriptional regulator of the proto-oncogene c-MYC in many cancer types (31,32,50,51) and also as regulator of post-transcriptional events such as translation (38) and mRNA stability (23). However, despite the fact that FUBP1 has been isolated in association with spliceosomal complexes (40) and includes four K homology domains (domains homologous to heterogeneous nuclear ribonucleoprotein K, a component of the spliceosomal H complexes (52)), its role in splicing regulation has remained speculative until recently.…”

“…7 and 8) sets the stage for alterations in splicing patterns in response to specific stimuli, wherein mechanisms antagonistic to FUBP1 may function to alter the splicing efficiency of specific exons and create alternative splice forms of MDM2. Role of FUBP1 in Cancer-FUBP1 itself is considered a protooncogene due to its role in the etiology of several types of cancer where it is overexpressed (23)(24)(25)(26)(27)(28). However, a small subset of oligodendrogliomas (a common brain malignancy) with "loss of function" mutations in FUBP1 has been identified where FUBP1 is considered a tumor suppressor (28 -30).…”

“…In this respect, it has been shown to function through both c-MYC-dependent and -independent pathways as a regulator of transcriptional and post-transcriptional events such as pre-mRNA translation (23,25,36,38,50,51,56,57). For instance, FUBP1 has inextricable ties with the p53 tumor-suppressor pathway through its transcriptional control of far upstream element-containing genes c-MYC and USP29 and also via its regulation of translation and stability of nucleophosmin and p21 mRNA (23,38,56,57). Additionally, the complex interactions of the various targets of FUBP1 among themselves or with other factors in the p53 pathway make FUBP1 an important player in this tumor-suppressor pathway (58,59).…”

“…FUBP1 is considered a proto-oncogene and is a biomarker for a variety of cancer types in which it is highly expressed, including hepatocellular carcinoma, non-small cell lung carcinoma, gliomas, and gastric cancer (23)(24)(25)(26)(27)(28). However, in oligodendrogliomas, where its expression is abolished due to mutations, FUBP1 is considered a tumor suppressor (28 -30).…”