The Roles of FHL3 in Cancer

Abstract

The four and a half LIM domain protein 3, also named the LIM-protein FHL3, belongs to the LIM-only family. Based on the special structure of LIM-only proteins, FHL3 can perform significant functions in muscle proliferation and cardiovascular diseases by regulating cell growth and signal transduction. In recent years, there has been increasing evidence of a relation between FHLs and tumor biology, since FHL3 is often overexpressed or downregulated in different cancers. On the one hand, FHL3 can function as a tumor suppressor and influence the expression of downstream genes. On the other hand, FHL3 can also play a role as an oncoprotein in some cancers to promote tumor progression via phosphorylation. Thus, FHL3 is proposed to have a dual effect on cancer progression, reflecting its complex roles in cancer. This review focuses on the roles of FHL3 in cancer progression and discusses the interaction of FHL3 with other proteins and transcription factors. Finally, the clinical significance of FHL3 for the treatment of cancers is discussed.

Keywords: LIM-only protein family; cancer treatment; four and a half LIM protein 3 (FHL3); tumor cell growth; tumor progression.

Figure 1

The gene encoding FHL3 is located on chromosome 1p34.3, at a locus between SF3A3 and UTP11. The initiation site is at base-pair 37956975 and the termination site is at base-pair 38031751. The gene has an overall length of 843 bp, with 5 introns and 6 exons.

Figure 2

Each member of the FHL protein family consists of four complete LIM domains and an N-terminal single zinc finger domain, the sequence of the latter corresponding to the C-terminal half of the LIM motif. Histidine and cysteine residues coordinate the binding of two Zn²⁺ ions per LIM domain, which helps stabilize the secondary and tertiary structure of FHL3 protein. Two isoforms of FHL3 are shown in the figure. Isoform 1 comprises 280 and isoform 2 comprises 172 amino acid residues.

Figure 3

FHL3 functions as an oncoprotein or tumor suppressor depending on the cellular context. It mediates the transduction of signaling pathways by interacting with other proteins, thereby controlling the expression of target genes. (A) In some contexts, FHL3 functions as a tumor promoter. FHL3 competitively binds GSK3β to interfere with Snail1 and Twist1 to inhibit the expression of its target gene, E-cadherin. Additionally, FHL3 activates Smad2, Smad3, and Smad4 via TGFβ to promote tumor growth. (B) In other contexts, FHL3 functions as a tumor suppressor. FHL3 promotes the phosphorylation and binding of Smad2 and Smad3 with CK1δ. Subsequently, the expression of the target genes, p21 and c-myc, can be decreased to inhibit tumor growth. SOX4 and SOX2 are also target genes that are downregulated to inhibit tumor growth. Additionally, FHL3 can inhibit cyclinsD1 and B1, affecting the G1 and G2 checkpoints. Moreover, FHL3 inhibits the expression and activity of VEGF by inhibiting HIF1α.