HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling

Abstract

BackgroundAndrogen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained.ResultsIn this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling.ConclusionsTaken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.

Prostate cancer in young men: an important clinical entity

“…Although most studies of prostate cancer genetics have typically included only a small proportion of men ≤ 55 years, the available evidence suggests that focusing efforts on these early onset cases, representing a population enriched for genetic susceptibility to prostate cancer, should provide the best opportunity for successfully identifying new variants. The potential value of this approach is illustrated by the recent discovery from our research team of a rare non-synonymous single-nucleotide polymorphism (SNP) in HOXB13 (G84E or rs138213197) , a transcription factor in early prostate development and differentiation 61 that has been implicated in androgen-independent prostate cancer cell growth 62 . Although the G84E allele was observed in unrelated prostate cancer cases, including those diagnosed at later age (minor allele frequency; MAF 0.6%), it was identified as a result of its significant enrichment in men with early onset prostate cancer (MAF 2.2%), and particularly among early onset cases with a family history of prostate cancer (MAF3.1%) 61 .…”

Cellular and molecular insights into Hox protein action

“…In addition, in androgen-responsive prostate cancer cell models, HOXB13 activity results in a decrease in pRb (retinoblastoma 1) phosphorylation, which then leads to pRb-E2F complex stabilisation and growth inhibition (Hamid et al, 2014). By contrast, HOXB13 can be overexpressed in androgen-refractory prostate tumours, stimulating tumour progression rather than being an oncosuppressor (Kim et al, 2010). In these tumours, HOXB13 appears to inhibit p21 (CDKN1A), which then allows E2F activation and cell cycle progression.…”

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

“…The HOXB13 protein is a sequence-specific, 284-amino acid transcription factor that interacts with androgen receptor and has an important role in prostate development (13). It has been shown to regulate cellular responses to androgens, such as promotion of androgen-independent growth in prostate cancer cell lines (14) by activating or repressing the expression of most androgen receptorresponsive genes (15). In addition to prostate cancer, HOXB13 has also been shown to have a role as a tumor suppressor in primary colorectal cancers (CRC; ref.…”