MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease

Abstract

Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored. Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression. These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time , and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the protumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFβ2. These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression. .

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

“…In the context of MYC's role as a universal transcriptional amplifier, a target gene of MYC-mediated repression could simply considered a technical anomaly reflecting unequal numbers of cells used for analysis [36]. However, we show that transcriptional signatures of MYC activity and MEIS1 are inversely correlated in two large independent cohorts, which is largely consistent with the finding that tumors and prostate cancer cells with increased MEIS1 expression show decreased enrichment of MYC target gene sets by GSEA [19]. Importantly, we further demonstrate here with ChIP-seq that the effects on MEIS1 expression are due in part to increased MYC occupancy at the MEIS1 locus, such that lower levels of MYC resulted in repositioning of MYC at specific sites.…”

“…Recently, Bhanvadia et al, postulated that higher MEIS1 expression conferred a less aggressive PCa phenotype [19]. Based on these results, we hypothesized that repression of MEIS1 expression by MYC contributes to MYC-driven PCa.…”

“…We sought to examine the genetic contribution of MYC to the development and progression of primary PCa in the context of dysregulated growth by using anti-MYC immunohistochemistry and performing laser capture microdissection on populations of human prostate tumor cells with varying 6 expression of MYC protein. We show using transcriptome profiling that increased MYC activity is inversely correlated with expression of Myeloid Ecotropic viral Insertion Site 1 (MEIS1), a transcription factor that interacts with and regulates the activity of HOX homeodomain transcription factors, including HOXB13 [18][19][20]. We determined that MYC binding to the MEIS1 locus decreases as MYC levels increases, and that MEIS1 expression is negatively correlated with HOXB13 expression and AR activity.…”

The role of WNT10B in normal prostate gland development and prostate cancer

“…To investigate clinical relevance, we queried an RNA-seq database of highly annotated localized PCa and metastatic castrate-resistant PCa specimens for WNT10B expression. 25 Similar to the metastatic cell lines, there was a significant increase in WNT10B mRNA in the metastatic specimens compared with the localized PCas ( Figure 4B). Furthermore, in metastatic castrate-resistant PCa specimens, there was a reduction in WNT10B expression following treatment with enzalutamide, abiraterone, or taxanes.…”

“…While the androgen‐independent metastatic PC3 cells expressed similar WNT10B as HuSLCs, a more aggressive variant, PC3M expressed higher levels of WNT10B than the parental PC3 line. To investigate clinical relevance, we queried an RNA‐seq database of highly annotated localized PCa and metastatic castrate‐resistant PCa specimens for WNT10B expression . Similar to the metastatic cell lines, there was a significant increase in WNT10B mRNA in the metastatic specimens compared with the localized PCas (Figure B).…”