HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation

Abstract

Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates b-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT -PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited b-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/b-catenin pathway.

Exploring the two-gene ratio in breast cancer—independent roles for HOXB13 and IL17BR in prediction of clinical outcome

“…The implication of the HOXB13 gene product in different types of cancer is beginning to be elucidated. It has been proposed as a marker for prostate cancer [18], and is also believed to be involved in endometrial cancer [19], cervical cancer [20], as well as renal cell carcinoma [21], and colorectal cancer [22]. In human cutaneous malignant melanoma with distant metastasis, the expression level of certain HOX genes, including HOXB13, was higher than in those melanoma patients without metastases [23], and in endometrial cancer cells, antisense-transfection of the HOXB13 gene reduced the invasive ability of the cells [19].…”

Epigenetic Silencing of Novel Tumor Suppressors in Malignant Melanoma

“…HOXB13 has been found to negatively regulate wound healing possibly by down-regulating hyaluronic acid (41, 42). HOXB13 was found to be down-regulated in prostate and colorectal cancer cells, where it has an antiproliferative role (43,44). More recently, HOXB13 was found to be epigenetically inactivated in a subset of renal cell carcinomas and had growthinhibitory effects in vitro (45).…”

Homeobox D10 Gene, a Candidate Tumor Suppressor, Is Downregulated through Promoter Hypermethylation and Associated with Gastric Carcinogenesis

“…The dysregulation of Hox genes may affect various pathways that play critical roles in tumorigenesis and cancer metastasis (19). Evidence shows that ectopic expression of HoxB13 in prostate and colon cancer cells can suppress tumor growth through downregulating of β-catenin-TCF pathway (17,23). It has been shown that HoxD10 expression is reduced in both breast and endometrial tumors (24).…”

“…In addition to their roles in development, numerous Hox genes (HoxB13, HoxA5 and HoxC6) have been found to be expressed aberrantly in a variety of solid tumors, including breast, colon and prostate cancers (16)(17)(18)(19)(20). Emerging evidence suggests that the expression of Hox genes is under epigenetic control (19)(20)(21)(22).…”