The cancer‐related Runx2 protein enhances cell growth and responses to androgen and TGFβ in prostate cancer cells

Abstract

Prostate cancer cells often metastasize to bone where osteolytic lesions are formed. Runx2 is an essential transcription factor for bone formation and suppresses cell growth in normal osteoblasts, but may function as an oncogenic factor in solid tumors (e.g., breast, prostate). Here, we addressed whether Runx2 is linked to steroid hormone and growth factor signaling, which controls prostate cancer cell growth. Protein expression profiling of prostate cell lines (i.e., PC-3, LNCaP, RWPE) treated with 5α-dihydrotestosterone (DHT) or TGFβ revealed modulations in selected cyclins, CDKs and CDK inhibitors that are generally consistent with mitogenic responses. Endogenous elevation of Runx2 and diminished p57 protein levels in PC-3 cells are associated with faster proliferation in vitro and development of larger tumors upon xenografting these cells in bone in vivo. To examine whether TGFβ or DHT signaling modulates the transcriptional activity of Runx2 and vice versa, we performed luciferase reporter assays. In PC-3 cells that express TGFβRII, TGFβ and Runx2 synergize to increase transcription of synthetic promoters. In LNCaP cells that are DHT responsive, Runx2 stimulates the Androgen Receptor (AR) responsive expression of the prostate-specific marker PSA, perhaps facilitated by formation of a complex with AR. Our data suggest that Runx2 is mechanistically linked to TGFβ and androgen responsive pathways that support prostate cancer cell growth.

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

“…3b, c) is consistent with similar results previously obtained with primary calvarial pre-osteoblasts [34, 55], MC3T3-E1 and C2C12 cells [56], as well as prostate cancer cells [36]. However, Runx2 was reported to promote proliferation in other contexts, including in PC3 prostate cancer cells [57] and mammary epithelial cells [58–60]. In fact, our results suggest not only a downregulation of some mitogenic signals but also an upregulation of other mitogenic signals such as Megf10, Calpain 6, and CMM5/CDC46 [61–63] (Table 2).…”

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

“…Our finding that RUNX2 may have functions in cell adhesion and motility of mobile osteosarcoma cells complements earlier findings obtained with both loss-of function and gain-of-function experiments in murine models (e.g. Runx2 null mouse embryonic fibroblasts and murine T cell lymphoma cells (14 -18)), as well as human breast and prostate cancer cells (45)(46)(47)(75)(76)(77)(78).…”

Differential Effects of RUNX2 on the Androgen Receptor in Prostate Cancer: Synergistic Stimulation of a Gene Set Exemplified by SNAI2 and Subsequent Invasiveness

“…Limited investigations of the reciprocal effects, those of RUNX2 on AR led to apparently conflicting results indicating either inhibition (29, 31) or stimulation (30, 32) of AR activity. To address the hypothesis that RUNX2 influences AR activity in a locus-dependent manner, we set out to characterize genome-wide the influence of RUNX2 on AR-regulated gene expression by comprehensive mRNA profiling of C4-2B/Rx2 dox PCa cells after activation of the AR with dihydrotestosterone (DHT) and/or induction of RUNX2 by doxycycline (dox).…”