PBX1

Official Full Name

PBX homeobox 1

Organism

Homo sapiens

GeneID

5087

Background

This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Studies in mice suggest that this gene may be involved in the regulation of osteogenesis and required for skeletal patterning and programming. A chromosomal translocation, t(1;19) involving this gene and TCF3/E2A gene, is associated with pre-B-cell acute lymphoblastic leukemia. The resulting fusion protein, in which the DNA binding domain of E2A is replaced by the DNA binding domain of this protein, transforms cells by constitutively activating transcription of genes regulated by the PBX protein family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2017]

Synonyms

CAKUHED;

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Detailed Information

Recent Research progress

PBX1, originally identified as a proto-oncogene of childhood leukemia, is a member of the TALE family of typical homeodomain transcription factors, whose members contain three residues inserted at the C-terminus of the homologous domain helix 1. As part of a heterologous oligomeric protein complex, PBX1 is thought to regulate the expression of developmental genes. However, PBX1 has recently been found to be overexpressed and its intracellular localization has been frequently amplified in many types of cancer.

PBX1 and ovarian cancer

It has been reported that in the clinical setting, high levels of PBX1 expression are associated with shorter survival in patients with ovarian cancer after chemotherapy. In tumor cells with low endogenous PBX1 levels, its forced expression promotes a cancer stem cell-like phenotype, most notably the increased resistance to platinum-based therapies most commonly used to treat the disease. In contrast, silencing PBX1 in platinum-resistant cells overexpressing PBX1 would make them susceptible to platinum treatment and reduce their stem-like properties. Analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to the promoter of genes involved in stem cell maintenance and tissue damage responses.

PBX1 and breast cancer

PBX1 plays a central role in regulating ERa transcription of epidermal growth factor (EGF) signaling. PBX1 regulates a subset of the EGF-ERa gene that is highly expressed in invasive breast tumors. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer demonstrated that elevated PBX1 protein levels are associated with early metastatic progression. Consistently, PBX1 protein levels are significantly up-regulated during metastasis in patients with ERa-positive breast cancer. The up-regulation of PBX1 in invasive tumors is mediated by genomic amplification of the PBX1 locus. Correspondingly, Era-positive breast cancer patients carrying PBX1 amplification have a poorer survival. Notably, PBX1 amplification can be identified in tumor-derived circulating free DNA from ERa-positive metastatic patients. PBX1 expanded metastatic patients also have shorter recurrence-free survival. The study data determined that PBX1 amplification is a functional marker of aggressive ERa-positive breast cancer. Mechanistically, PBX1 amplification affects several key pathways associated with aggressive ERa-positive breast cancer.

PBX1 and gastric carcinoma

Current studies indicate increased expression of PBX1 in GC tissue compared to adjacent normal tissues. This increase in PBX1 expression levels is inversely correlated with HOXB9 mRNA expression and is also associated with malignancy and metastasis. PBX1 promotes the proliferation and metastasis of GC cells both in vitro and in vivo. These phenomena are also accompanied by epithelial to mesenchymal transition (EMT). In addition, PBX1 promotes tumor growth and expression of angiogenic factors. The complex structural model of PBX1-HOX suggests that EMT induction may require hydrophobic binding between PBX1 and the hexapeptide motif. This analysis also revealed that the Phe(252) residue in the first helix of the TALE homeodomain is involved in the hydrophobic binding reaction of the latter. In vitro data from the PBX1 mutant indicated that PBX1 failed to promote tumorigenesis of GC cells by EMT induction when the Phe(252) residue lost its hydrophobicity. The presence of this residue may be critical to promoting hydrophobic binding to the hexapeptide motif. These findings suggest that PBX1 may be a potential target for GC therapy, and this study provides a platform to elucidate the molecular mechanisms by which PBX1 plays a role in GC tumorigenesis.

PBX1 and ccRCC

The expression of PBX1 was significantly up-regulated in clear cell renal cell carcinoma(ccRCC) compared to adjacent normal tissues, and the overall survival rate of the high PBX1 group was significantly lower than that of the low PBX1 group. Furthermore, JAK2 expression was significantly associated with PBX1 expression in human clinical samples, and PBX1 knockdown inhibited STAT3 phosphorylation and decreased transcription of the STAT3 target gene Cyclin D1. More interestingly, PBX1 knockdown inhibits ccRCC cell viability, proliferation and cell cycle progression in vivo and in vitro. Therefore, PBX1 plays a carcinogenic role in ccRCC through the JAK2/STAT3 pathway and indicates its potential application in the future treatment of human ccRCC.

In summary, current research indicates that PBX1 is expressed in a variety of cancers. Therefore, further study of the function of PBX1 and its important role in the mechanism of tumorigenesis is of great significance and value for the diagnosis and treatment of cancer.

References:

Jung JG, et al. Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1. Cancer Research, 2016, 76(21):6351-61
Magnani Luca, et al. The pioneer factor PBX1 is a novel driver of metastatic progression in ER'-positive breast cancer. Oncotarget, 2015, 6(26): 21878-21891
Wang Jun, et al. Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer. International Journal Of Cancer, 140(11): 2484-2497
Changyu He, et al. A hydrophobic residue in the TALE homeodomain of PBX1 promotes epithelial-to-mesenchymal transition of gastric carcinoma. Oncotarget, 2017, 8(29):46818-46833
Wei Xin, et al. PBX1 promotes the cell proliferation via JAK2/STAT3 signaling in clear cell renal carcinoma. Biochemical and Biophysical Research Communications. 2018, 500(3):650-657

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