TWIST modulates prostate cancer cell-mediated bone cell activity and is upregulated by osteogenic induction.
TWIST, a helix-loop-helix transcription factor, is highly expressed in many types of human cancer. We have previously found that TWIST confers prostate cancer cells with an enhanced metastatic potential through promoting epithelial-mesenchymal transition (EMT) and a high TWIST expression in human prostate cancer is associated with an increased metastatic potential. The predilection of prostate cancer cells to metastasize to bone may be due to two interplaying mechanisms (i) by increasing the rate of bone remodeling and (ii) by undergoing osteomimicry. We further studied the role of TWIST in promoting prostate cancer to bone metastasis. TWIST expression in PC3, a metastatic prostate cancer cell line, was silenced by small interfering RNA and we found that conditioned medium from PC3 with lower TWIST expression had a lower activity on stimulating osteoclast differentiation and higher activity on stimulating osteoblast mineralization. In addition, we found that these effects were, at least partly, associated with TWIST-induced expression of dickkopf homolog 1 (DKK-1), a factor that promotes osteolytic metastasis. We also examined TWIST and RUNX2 expressions during osteogenic induction of an organ-confined prostate cancer cell, 22Rv1. We observed increased TWIST and RUNX2 expressions upon osteogenic induction and downregulation of TWIST through short hairpin RNA reduced the induction level of RUNX2. In summary, our results suggest that, in addition to EMT, TWIST may also promote prostate cancer to bone metastasis by modulating prostate cancer cell-mediated bone remodeling via regulating the expression of a secretory factor, DKK-1, and enhancing osteomimicry of prostate cancer cells, probably, via RUNX2.
Yuen
Hiu-Fung
HF
Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Kwok
Wai-Kei
WK
Chan
Ka-Kui
KK
Chua
Chee-Wai
CW
Chan
Yuen-Piu
YP
Chu
Ying-Ying
YY
Wong
Yong-Chuan
YC
Wang
Xianghong
X
Chan
Kwok-Wah
KW
D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000503:physiopathology*; D002113:Calcification, Physiologic; D002460:Cell Line; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D017931:DNA Primers; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D010957:Plasmids; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics*; D015854:Up-Regulation
D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C493709:RUNX2 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000469:Alkaline Phosphatase