| Description | The open reading frame encodes a 279 amino acid protein with an estimated molecular weight of 32.2kDa. FHL2 protein constitutes four and a half N-terminal LIM domains. The four complete LIM domains extend from amino acid 40-92, 100-153, 162-217 and 220-275. |
| Expression | In human tissues, FHL2 expression is the most abundant in adult heart and ovary, and of low level in brain, lung, liver, kidney and intestine. FHL2 is initially identified as a downregulated gene in human rhabdomyosarcoma cells. However, elevated FHL2 expression is detected in other cancers, including hepatocellular carcinoma, glioblastoma, breast, prostate, ovarian, and gastrointestinal cancers. |
| Localisation | Cytoplasm and nucleus. |
| Function | At tissue level, FHL2 plays important roles in the development of cardiac circulatory system and placenta. It also induces osteoblast and myoblast differentiation. At cellular level, FHL2 participates in various processes, including cell survival, adhesion, motility, transcription and signal transduction. At molecular level, the LIM domains of FHL2 are double zinc finger motifs that physically interact with partner proteins to modulate RNA splicing, DNA replication and repair. It also functions as a transcriptional co-activator for androgen receptor, AP-1, CREB (cAMP response element binding protein), CREM (cAMP response element modulator), BRCA1 (breast cancer 1), WT-1 (wilms' tumor), and NF-kB (nuclear factor-kB). Moreover, FHL2 is a transcriptional co-suppressor for ERK2 (extracellular signal regulated kinase 2), SRF and FOXO1 (forkhead box O1). |
| Homology | FHL2 belongs to the four-and-a-half-LIM-only protein family, which includes FHL1, FHL2, FHL3, FHL4 and FHL5 (ACT). Human FHL2 amino acid sequence is 48.2% identical with FHL1, 53.4% with FHL3, 48.4% with mouse FHL4, and 59.1% with FHL5. Orthologs of human FHL2 are found in macaque, mouse, rat, bovine, dog, chicken, frog, zebrafish, amphioxis, drosophila and C. elegans. |
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| Entity | Rhabdomyosarcoma |
| Note | FHL2 expression is downregulated in rhabdomyosarcoma cells relative to normal myoblasts (Genini et al., 1997). |
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| Entity | Hepatocellular carcinoma |
| Note | In 8 of 10 human liver tumors samples, FHL2 mRNA expression is higher than that in matched nontumor livers (Wei et al., 2003). In contrast, it is recently reported that FHL2 protein is downregulated in liver tumors, as compared with matched nontumor liver tissues. In addition, FHL2 inhibits hepatoma cell growth in vitro and in nude mice (Ding et al., 2009). |
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| Entity | Ovarian cancer |
| Note | FHL2 protein expression is upregulated in epithelial ovarian cancer, as compared with matched normal tissues (Gabriel et al., 2004). |
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| Entity | Breast cancer |
| Note | FHL2 is overexpressed in human mammary carcinoma samples, compared with normal breast tissues. FHL2 induces the expression of cell cycle inhibitor p21Cip1/Waf1 in MDA-MB 231 breast cancer cells (Martin et al., 2007). |
| Prognosis | Patients with tumors expressing low amounts of FHL2 were characterized by a significantly better survival compared to those with high intratumoral FHL2 expression (Gabriel et al., 2006). |
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| Entity | Prostate cancer |
| Note | FHL2 expression is downregulated by 2- to 4-fold in primary prostate cancer relatively to normal tissues for five pairs of samples (Kinoshita et al., 2005). Another study reports that FHL2 expression is increased in prostate adenocarcinoma cells when compared with benign epithelial cells. It might be the subcellular localization of FHL2 that governs the progression of prostate cancer (Muller et al., 2002). Androgen-induced FHL2 expression is mediated by SRF (Heemers et al., 2007). |
| Prognosis | Nuclear, but not cytoplasmic expression of FHL2 significantly correlates with the recurrence of prostate cancer (Kahl el al., 2006). |
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| Entity | Gastrointestinal cancer |
| Note | FHL2 expression is upregulated in gastric and colon cancer, compared with matched normal tissues. Suppression of FHL2 induces gastric and colon cell differentiation, and inhibits cell proliferation and expression of oncogenes (survivin, cox-2, hTERT and c-jun) in vitro. Antisense FHL2 also inhibits tumorigenesis of colon cancer cells in xenograft nude mice model (Wang et al., 2007). |
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| Entity | Glioma |
| Note | The mRNA level of FHL2 is elevated in both low (3 of 6) and high (11 of 13) grade glioma patient samples. FHL2 induces glioblastoma cell proliferation and migration in vitro, and promotes tumorigenesis in glioblastoma xenograft nude mice model. Overexpression of FHL2 decreases mRNA levels of p53 and its downstream proapoptotic genes, and enhances promoter activities of AP-1, human telomerase reverse transcriptase and survivin genes (Li et al., 2008). |
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| Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy. |
| Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Manatsu SI, Sasaoka T, Izumi T, Bonne G, Schwartz K, Kimura A. |
| Biochem Biophys Res Commun. 2007 May 25;357(1):162-7. Epub 2007 Mar 30. |
| PMID 17416352 |
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| Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart. |
| Chan KK, Tsui SK, Lee SM, Luk SC, Liew CC, Fung KP, Waye MM, Lee CY. |
| Gene. 1998 Apr 14;210(2):345-50. |
| PMID 9573400 |
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| Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. |
| Ding L, Wang Z, Yan J, Yang X, Liu A, Qiu W, Zhu J, Han J, Zhang H, Lin J, Cheng L, Qin X, Niu C, Yuan B, Wang X, Zhu C, Zhou Y, Li J, Song H, Huang C, Ye Q. |
| J Clin Invest. 2009 Feb;119(2):349-61. doi: 10.1172/JCI35930. Epub 2009 Jan 12. |
| PMID 19139564 |
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| Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study. |
| Gabriel B, Fischer DC, Orlowska-Volk M, zur Hausen A, Schule R, Muller JM, Hasenburg A. |
| J Soc Gynecol Investig. 2006 Jan;13(1):69-75. |
| PMID 16378916 |
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| Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer. |
| Gabriel B, Mildenberger S, Weisser CW, Metzger E, Gitsch G, Schule R, Muller JM. |
| Anticancer Res. 2004 Mar-Apr;24(2B):921-7. |
| PMID 15161045 |
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| Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma. |
| Genini M, Schwalbe P, Scholl FA, Remppis A, Mattei MG, Schafer BW. |
| DNA Cell Biol. 1997 Apr;16(4):433-42. |
| PMID 9150430 |
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| Androgen induction of the androgen receptor coactivator four and a half LIM domain protein-2: evidence for a role for serum response factor in prostate cancer. |
| Heemers HV, Regan KM, Dehm SM, Tindall DJ. |
| Cancer Res. 2007 Nov 1;67(21):10592-9. |
| PMID 17975004 |
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| The multifunctional roles of the four-and-a-half-LIM only protein FHL2. |
| Johannessen M, Moller S, Hansen T, Moens U, Van Ghelue M. |
| Cell Mol Life Sci. 2006 Feb;63(3):268-84. (REVIEW) |
| PMID 16389449 |
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| Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. |
| Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schule R, Buettner R. |
| Cancer Res. 2006 Dec 1;66(23):11341-7. |
| PMID 17145880 |
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| Differently regulated androgen receptor transcriptional complex in prostate cancer compared with normal prostate. |
| Kinoshita M, Nakagawa T, Shimizu A, Katsuoka Y. |
| Int J Urol. 2005 Apr;12(4):390-7. |
| PMID 15948728 |
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| The biological relevance of FHL2 in tumour cells and its role as a putative cancer target. |
| Kleiber K, Strebhardt K, Martin BT. |
| Anticancer Res. 2007 Jan-Feb;27(1A):55-61. (REVIEW) |
| PMID 17352216 |
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| The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities. |
| Li M, Wang J, Ng SS, Chan CY, Chen AC, Xia HP, Yew DT, Wong BC, Chen Z, Kung HF, Lin MC. |
| Glia. 2008 Sep;56(12):1328-38. |
| PMID 18615633 |
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| FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells. |
| Martin BT, Kleiber K, Wixler V, Raab M, Zimmer B, Kaufmann M, Strebhardt K. |
| Cell Cycle. 2007 Jul 15;6(14):1779-88. |
| PMID 17682292 |
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| The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. |
| Muller JM, Metzger E, Greschik H, Bosserhoff AK, Mercep L, Buettner R, Schule R. |
| EMBO J. 2002 Feb 15;21(4):736-48. |
| PMID 11847121 |
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| Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. |
| Wang J, Yang Y, Xia HH, Gu Q, Lin MC, Jiang B, Peng Y, Li G, An X, Zhang Y, Zhuang Z, Zhang Z, Kung HF, Wong BC. |
| Gastroenterology. 2007 Mar;132(3):1066-76. Epub 2006 Dec 3. |
| PMID 17383428 |
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| Identification of the LIM protein FHL2 as a coactivator of beta-catenin. |
| Wei Y, Renard CA, Labalette C, Wu Y, Levy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA. |
| J Biol Chem. 2003 Feb 14;278(7):5188-94. Epub 2002 Dec 3. |
| PMID 12466281 |
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