The transcription factor CUX1 negatively regulates invasion in castrate resistant prostate cancer

Abstract

Metastatic prostate cancer is treated with androgen ablation therapy but progress to castrate resistant prostate cancer (CRPC). This study aimed to investigate the role of CUX1 in CRPC using clinical samples and in vitro models. CUX1 expression was increased in androgen-independent cells compared to androgen-sensitive cells. The multi-isoform nature of CUX1 makes it difficult to assay in tissue microarrays as there is no epitope able to distinguish the many isoforms for immunohistochemistry. Using surrogate markers, we found no differential expression between castrate resistant and local hormone naïve tissue. However, differences have been demonstrated at the transcript level. In androgen-sensitive cells, migration, but not invasion, increased following CUX1 knockdown. Conversely, in androgen-independent cells, invasion was increased. This observed difference in invasion capacity is not E-cadherin mediated, as CUX1 knockdown increases the expression of E-cadherin in both cell lines with no inter-cell line difference. Cells expressed different ratios of p110/p200 isoforms depending on androgen status and cathepsin L was only detectable in androgensensitive cells. MMP3 is upregulated in the androgen-independent cells. Rather than a simple presence or absence of CUX1, the relative balance of CUX1 isoforms and their interplay may be a significant factor in the functional role of CUX1 in CRPC.

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation

“…Knock-down of p200 in these cathepsin L-negative cells enhanced rather than suppressed invasiveness. This indicates that p110 promotes tumor progression, whereas p200, in the absence of cathepsin L, might exert tumor-suppressive actions [ 47 ]. It may be hypothesized that the delayed but also tumor-promoting phenotype seen in our p200 CUX1 mouse model is mediated by cathepsin L converting p200 into the active, tumor-promoting p110 variant.…”

CUX1, A Controversial Player in Tumor Development

“…More importantly, a comprehensive study by interrogating total 7,651 genome sequences derived from 28 tumor types revealed nonsense and frameshift mutations in CUX1 in 1-5% of tumors and found that CUX1 deficiency can lead to activation of the pro-oncogenic PI3K-AKT signaling (93). In addition, CUX1 has been shown to negatively regulate invasion in castrate-resistant prostate cancer (94) and multidrug resistance in gastric cancer (95). It is worth mentioning that, although loss and/or inactivation of a CUX1 allele have been documented in many studies, there is so far no case of a tumor where both alleles have been lost or inactivated, suggesting the coexistence of an inactivated and an activated CUX1 alleles in tumor cells.…”

Genomic studies controvert the existence of the CUX1 p75 isoform

“…While p200 CUX1 protein increases after TGF-β treatment in normal lung fibroblasts, p75 does not 49 . Finally, in a study that reported that androgen-resistant prostate cancer cell lines upregulate p200, p75 was unchanged 50 . Collectively, these studies either fail to document an endogenous p75 protein, or uncouple the biology of p200 from p75.…”