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Review
. 2013 Nov 25;14(12):23231-43.
doi: 10.3390/ijms141223231.

The homeobox only protein homeobox (HOPX) and colorectal cancer

Keishi Yamashita  1 , Hiroshi Katoh, Masahiko Watanabe
Affiliations
Review

The homeobox only protein homeobox (HOPX) and colorectal cancer

Keishi Yamashita et al. Int J Mol Sci. .

Abstract

The HOP (homeobox only protein) homeobox (HOPX) is most closely related to the homeobox protein that contains a homeobox-like domain but lacks certain conserved residues required for DNA binding. Here, we review the current understanding of HOPX in the progression of colorectal cancer (CRC). HOPX was initially reported as a differentiation marker and is expressed in various normal tissues. In the colon, HOPX is expressed uniquely in the quiescent stem cell, +4, and in differentiated mucosal cells of the colon. HOPX expression is markedly suppressed in a subset of cancers, mainly in an epigenetic manner. CRC may include separate entities which are differentially characterized by HOPX expression from a prognostic point of view. HOPX itself can regulate epigenetics, and defective expression of HOPX can result in loss of tumor suppressive function and differentiation phenotype. These findings indicate that HOPX may be both a central regulator of epigenetic dynamics and a critical determinant for differentiation in human cells. HOPX downstream targets were identified in CRC cell lines and hold promise as candidates for therapeutic targets of CRC, such as EphA2 or AP-1. Further analysis will elucidate and confirm the precise role of such proteins in CRC progression.

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Figures

Figure 1.
Figure 1.
(a) Sequence comparison of the homeodomain of mouse homeobox only protein (HOP) with other homeodomains. Amino acid positions within the 60 amino acid homeodomain are shown; (b) Solution Structure of the Homeodomain-only Protein HOP from NCBI structure summery; (c) HOP homeobox (HOPX) expression in the normal colonic mucosa (left). HOPX peptide is absorbed to eliminate non-specific staining of HOPX (right); (d) HOPX expression was suppressed in colon cancer with promoter DNA hypermethylation, while its expression was sustained in colon cancer with no methylation. Scale bar, 100 μm.
Figure 2.
Figure 2.
Model depicting Hdac2 interacting with Hopx to induce deacetylation of Gata4 and modulation of cell cycle genes (left); Model depicting serum response factor (SRF) interacting with Hopx to suppress SRF transcriptional activity and modulation of growth related genes (middle); Model depicting enhancer of polycomb 1 (EPC1) interacting with Hopx to induce differentiation related genes (right).
Figure 3.
Figure 3.
(a) Chromosomal location of HOPX; (b) Schematic diagram of the three spliced transcript variants and a common transcript core in HOPX (top) and of CpG islands (dark areas) in the 5′-flanking region of HOPX gene (bottom). The only HOPX-β harbors CpG islands encompassing the first exon and intron. Vertical bars indicate the dinucleotide CpGs.
Figure 4.
Figure 4.
DNA microarray identified downstream targets of HOPX. Cell surface proteins such as EphA2 and EMP1, angiongenic growth factor of Cyr61, transcriptional factor such as c-Fos, EGR1, and metabolism-related genes like GLUT3 and NPC1 were tabulated.
Figure 5.
Figure 5.
Model depicting HOPX-silenced cancer cells (left red cell) to induce EphA2, EMP1, c-fos, EGR1, and Cyr61, and result in metastatic formation. Transcription factors AP-1 and EGR1 may further induce cancer invasion and metastasis putatively through induction of matrix metalloproteinases and angiogenic growth factors. On the other hand, cancer cells with HOPX expression (right green cell) suppress such oncogenic molecules, and result in attenuation of invasive and metastatic properties like normal cells (right green cell). Green cells represent attenuation of invasive and metastatic properties against red cells that exhibited highly invasive and metastatic potential.
Figure 6.
Figure 6.
HOPX is a specific marker of the quiescent stem cells (+4), while Lgr-5 is a specific marker of the active stem cells (CBC) of the colon goblets.
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