Collaboration of Kras and androgen receptor signaling stimulates EZH2 expression and tumor-propagating cells in prostate cancer.
Elevation of the chromatin repression factor enhancer of zeste homolog (EZH2) is associated with progression and poor prognosis in several human cancers including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor, Kras, and Akt, which drives three of the most frequently activated oncogenic signaling pathways in prostate cancer. Although, any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of androgen receptor and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo. Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical.
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA. cai@musc.edu
Houjian
H
Cai
Sanaz
S
Memarzadeh
Tanya
T
Stoyanova
Zanna
Z
Beharry
Andrew S
AS
Kraft
Owen N
ON
Witte
D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D011944:Receptors, Androgen; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)