title: Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM.
abstract: The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3'UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3'-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heath
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cher
authors.forename: Isaac
authors.initials: I
authors.lastname: Powell
authors.forename: Lance
authors.initials: L
authors.lastname: Heilbrun
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Seema
authors.initials: S
authors.lastname: Sethi
authors.forename: Oudai
authors.initials: O
authors.lastname: Hassan
authors.forename: Clara
authors.initials: C
authors.lastname: Hwang
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gupta
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Chitale
authors.forename: Wael A
authors.initials: WA
authors.lastname: Sakr
authors.forename: Mani
authors.initials: M
authors.lastname: Menon
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: C512018:1,1-bis(3'-indolyl)methane; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007211:Indoles; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; C487931:mirnlet7 microRNA, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2