Four and a half LIM domains protein 1 can be as a double-edged sword in cancer progression

Abstract

Four and a half LIM domains protein 1 (FHL1), as the name suggests, contains four and a half LIM domains capable of interacting with various molecules, including structural proteins, kinases, and transcriptional machinery. FHL1 contains a zinc-finger domain and performs diverse roles in regulation of gene transcription, cytoarchitecture, cell proliferation, and signal transduction. Several studies have validated the importance of FHL1 in muscle development, myopathy, and cardiovascular diseases. Mutations in the FHL1 gene are associated with various myopathies. Recently, FHL1 was identified as a major host factor for chikungunya virus (CHIKV) infection in both humans and mice. Based on more recent findings over the last decade, FHL1 is proposed to play a dual role in cancer progression. On the one hand, FHL1 expression is suppressed in several cancer types, which correlates with increased metastatic disease and decreased survival. Moreover, FHL1 is reported to inhibit tumor cell growth and migration by associating with diverse signals, such as TGF-β and ER, and therefore considered a tumor suppressor. On the other hand, FHL1 can function as an oncogenic protein that promotes tumor progression upon phosphorylation, reflecting complex roles in cancer. This review primarily focuses on the dual role and underlying mechanisms of action of FHL1 in human cancer progression and its clinical relevance.

Keywords: Four and a half LIM protein 1 (FHL1); metastasis; tumor cell growth.

Figure 1

Structure and homology of FHL1 proteins. FHL1A contains four complete and an N-terminal half LIM domain. FHL1B contains the N-terminal three and a half LIM domains identical to FHL1A. However, in this case, the C-terminus is replaced by three nuclear localization signals (NLS), a nuclear export sequence (NES), and a binding site for RBP-Jκ. FHL1C comprises the N-terminal two and a half LIM domains identical to FHL1A and FHL1B, followed by a C-terminal RBP-Jκ-binding domain.

Figure 2

FHL1 functions as a tumor suppressor. FHL1 interacts with Smad2, Smad3, and CK1δ in hepatocellular carcinoma cells, and enhances phosphorylation of Smad proteins and nuclear translocation of Smad4 to regulate downstream target genes, such as p21 and c-myc. In human breast cancer cells, FHL1 interacts directly with ERα or inhibits AKT to decrease transcriptional activity of ERα, resulting in suppression of estrogen target gene expression, including pS2 and cathepsin D52. Furthermore, RIP140 cooperates with ER to inhibit estrogen signaling and estrogen-responsive target gene transcription. FHL1 inhibits HIF-1 transcriptional activity by competing with HIF-1 for binding to the co-activators, p300/CBP48, or blocking HIF1α-HIF1β heterodimerization. Levels of G1 and G2/M phase-related proteins, including cyclin A, B1, D, and E, are suppressed by FHL1 to mediate G1 and G2/M cell cycle arrest in lung cancer cells.

Figure 3

Phosphorylated FHL1 functions as a tumor promoter. Src interacts with and phosphorylates FHL1, which immediately trigrers translocation into the nucleus. Phosphorylated FHL1 binds to and cooperates with nucelar transcription factor BCL, promoting tumor cell growth. However, in the presence of excessive cellular Kindlin-2, FHL1 is recruited to focal adhesion sites and forms a complex with Kindlin-2 and Src. Interactions between Src and FHL1 and subsequent Src-induced phosphorylation of FHL1 are suppressed in this state, which maintains the tumor suppressive role of FHL1.