Overexpression of far upstream element binding proteins: A mechanism regulating proliferation and migration in liver cancer cells

Abstract

Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins ( M icrotubules are cytoplasmic components of the cytoskeleton that play a critical role in the maintenance of cell morphology, division, intracellular transport, and motility. Microtubule polymers consist of ␣-and ␤-tubulin heterodimers and are characterized by continuous transition between phases of shrinkage (depolymerization/catastrophe) and elongation (polymerization/rescue). This dynamic instability is regulated by several factors, including microtubule-associated proteins and microtubule destabilizers such as stathmin. 1 The cytosolic phosphoprotein stathmin (oncoprotein 18) is expressed in most proliferating cells, and its concentration increases during the S-phase of the cell cycle. In this context, stathmin facilitates microtubule shortening by tubulin sequestration and active promotion of microtubule catastrophe, depending on the sequential phosphorylation status of four serine residues. 2 When cells enter mitosis, stathmin is inactivated by phosphorylation, allowing the formation of the mitotic spindle; subsequent reactivation of stathmin by dephosphorylation is necessary for the exit from mitosis. 1

FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53

“…Another cell factor, nucleophosmin (NMP), which interacts with p21 and contributes to the stability of p21 and p53 (75,76), is suppressed by FBP1 (63). FBP1 also is known as a positive regulator of Stathmin, a microtubule destabilizing protein that influences proliferation and migration of cancer cells (14,45). Stathmin is a potential target of p53 transcriptional repression (77); its overexpression is necessary for the survival of cancer cells (78).…”

“…In approximately 80% of HCC tumors, FBP1 is overexpressed, and its expression in tumor cells is linked to poor patient survival (14,15). p53 in a Huh7-derived cell line carries a mutation at codon 220 (Y220C).…”

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

“…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).…”

“…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).…”

Far upstream element-binding protein 1 and RNA secondary structure both mediate second-step splicing repression

“…For example, two groups observed elevated expression of FUBP1 in more than 70% of human hepatocellular carcinoma (HCC) samples and also provided evidence that FUBP1 plays an important role in tumor growth (47,48). Notably, they also revealed no significant correlations between FUBP1 and MYC expression in HCC cells, suggesting that FUBP1-dependent regulation of MYC plays a minor role in hepatocarcinogenesis, although evidence for a role in renal carcinomas has been presented (49).…”