Article

Oncogene Functions of FHL2 Are Independent from NF-κBIα in Gastrointestinal Cancer

University of Hong Kong, Queen Mary Hospital Department of Medicine Hong Kong China
Pathology & Oncology Research (Impact Factor: 1.86). 03/2009; 15(1):31-36. DOI: 10.1007/s12253-008-9085-1

ABSTRACT

Four and a half of LIM-only protein 2 (FHL2) is an adaptor protein that can interact with many transcription factors and thus
plays a variety of biological functions. Previous studies by our group have demonstrated that suppression of FHL2 was capable
of inducing tumor cell differentiation, and inhibiting the growth of experimental gastric and colon cancers. Therefore, FHL2
appears to function as an oncogene. In order to further explore the mechanisms of how FHL2 is involved in tumorigenesis, we
attempted to test whether FHL2 has any direct association with nuclear factor (NF-κB), the most important transcription factor
involved in apoptosis, inflammation, and carcinogenesis. Using an Yeast Two Hybrid (Y2H) screening system, we have shown that
FHL2 may have an interaction with NF-κBIα, the coding gene for IκBα which is the most potent endogenous inhibitor for NF-κB
activation. However, subsequent studies using co-immunoprecipitation and co-localization failed to confirm the Y2H finding.
Down-regulation of FHL2 by FHL2-siRNA down-regulated the expression of NF-κB p65. We therefore concluded that under the physiological
condition, FHL2 may activate NF-κB pathway, even though such an activation may not be mediated by a direct binding of FHL2
to NF-κB inhibitor protein IκB.

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    Preview · Article · Apr 2010 · Oncology Reports
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    ABSTRACT: Four and a half LIM domain protein 2 (FHL2) can interact with many proteins and regulates different cellular processes, including proliferation and differentiation. FHL2 expression is often deregulated in cancer and may act as both tumor-promoter or tumor-suppressor depending on the type of cancer. Thus, a previous study found that increased FHL2 expression in colon cancer and suppression of FHL2 in a colon cancer cell line with endogenously high FHL2 expression inhibited tumor growth. We applied the opposite strategy, an FHL2 expression plasmid was stably transfected into HT-29 cells, a colon carcinoma cell line which exhibits very low basal levels of FHL2. Stable expression of FHL2 in HT-29 cells induced a G2/M arrest and inhibited anchorage-dependent and -independent growth in vitro. Further, FHL2 expressing HT-29 cell clones revealed significantly higher expression of the differentiation marker E-cadherin but reduced activity of the transcription factor NF-kappaB, which is known to promote colon cancer progression. These findings further underscore the complex role of FHL2 in tumorigenicity, with even different effects on cellular functions of cancer cell lines derived from the same type of tumor and distinctly suggest caution regarding therapeutic strategies targeting FHL2 to treat (colon) cancer.
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    ABSTRACT: XIAP-associated factor 1(XAF1) is a tumor suppressor with its functional mechanisms not fully understood. The zinc-finger cluster located at the N-terminus is the only domain structure. Four and a half LIM domain protein 2 (FHL2) also contains a tandem zinc finger structure, and its protein functions as an important adaptor and modifier in protein–protein interactions. Both of their structures are relatively simple, while the association between them is still unclear. In this study, we detected the interaction between XAF1 and FHL2 by using the yeast two-hybrid system. We identified FHL2 as a XAF1 binding protein. Furthermore, both XAF1 and FHL2 localized to the cytoplasm, mitochondria, and nucleus of gastric cancer cells. Over-expression of XAF1 excluded FHL2 from the nucleus and suppressed the trans-activity of FHL2 in stimulating the transcriptional activities of β-catenin and AP-1. In conclusion, our findings unraveled an antagonistic mechanism between a tumor suppressor and an oncoprotein in cancer cells. Mol. Carcinog. © 2010 Wiley-Liss, Inc.
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