title: Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression.
abstract: The histone methyltransferase EZH2 is a central epigenetic regulator of cell survival, proliferation, and cancer stem cell (CSC) function. EZH2 expression is increased in various human cancers, including highly aggressive pancreatic cancers, but the mechanisms underlying for its biologic effects are not yet well understood. In this study, we probed EZH2 function in pancreatic cancer using diflourinated-curcumin (CDF), a novel analogue of the turmeric spice component curcumin that has antioxidant properties. CDF decreased pancreatic cancer cell survival, clonogenicity, formation of pancreatospheres, invasive cell migration, and CSC function in human pancreatic cancer cells. These effects were associated with decreased expression of EZH2 and increased expression of a panel of tumor-suppressive microRNAs (miRNA), including let-7a, b, c, d, miR-26a, miR-101, miR-146a, andmiR-200b, c that are typically lost in pancreatic cancer. Mechanistic investigations revealed that reexpression of miR-101 was sufficient to limit the expression of EZH2 and the proinvasive cell surface adhesion molecule EpCAM. In an orthotopic xenograft model of human pancreatic cancer, administration of CDF inhibited tumor growth in a manner associated with reduced expression of EZH2, Notch-1, CD44, EpCAM, and Nanog and increased expression of let-7, miR-26a, and miR-101. Taken together, our results indicated that CDF inhibited pancreatic cancer tumor growth and aggressiveness by targeting an EZH2-miRNA regulatory circuit for epigenetically controlled gene expression.
authors: Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
authors: Bin
authors: B
authors: Bao
authors: Shadan
authors: S
authors: Ali
authors: Sanjeev
authors: S
authors: Banerjee
authors: Zhiwei
authors: Z
authors: Wang
authors: Farah
authors: F
authors: Logna
authors: Asfar S
authors: AS
authors: Azmi
authors: Dejuan
authors: D
authors: Kong
authors: Aamir
authors: A
authors: Ahmad
authors: Yiwei
authors: Y
authors: Li
authors: Subhash
authors: S
authors: Padhye
authors: Fazlul H
authors: FH
authors: Sarkar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D003474:Curcumin