Abstract
The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.
Highlights
Prostate cancer (PrCa) is the fifth leading cause of cancer-related death in men worldwide and is responsible for the highest incidence of male cancer in the United States (Ferlay et al, 2015; Siegel et al, 2019)
Our previous studies demonstrated that expression of both MEIS1 and MEIS2 is frequently decreased in PrCa patients and that MEIS-positive tumors confer an overall lower risk of biochemical recurrence and metastasis (Bhanvadia et al, 2018; Chen et al, 2012)
MEIS2 is known to have several isoforms that differ mainly in the exons used at the C-terminus, as well as one homeodomain-less variant known as MEIS2E (Figure 1—figure supplement 1A; Geerts et al, 2005)
Summary
Prostate cancer (PrCa) is the fifth leading cause of cancer-related death in men worldwide and is responsible for the highest incidence of male cancer in the United States (Ferlay et al, 2015; Siegel et al, 2019). It can be difficult to distinguish which men harbor indolent or aggressive tumors (Culig, 2014), in patients with intermediate Gleason scores (Gearman et al, 2018). These features of PrCa pose a significant clinical problem. One novel pathway to understand tumor etiology and disease progression as well as develop new treatments is through HOXB13, which exhibits germline mutation in a subset of familial PrCa. HOXB13 is the predominant HOX factor that drives development and differentiation of prostate epithelial cells (Brechka et al, 2017).
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