Curcumin analog CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression
Menée in vitro et à l'aide d'une xénogreffe orthotopique de cancer humain du pancréas, cette étude montre qu'un analogue de la curcumine, une épice issue de la plante herbacée "curcuma", inhibe la croissance tumorale en augmentant le niveau d'expression de micro-ARNs suppresseurs de tumeur et en réduisant le niveau d'expression de l'histone méthyltransférase EZH2
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 (PC), but the mechanisms underlying for its biological effects are not yet well understood. In this study we probed EZH2 function in PC using CDF, a novel analog of the turmeric spice component curcumin that has anti-oxidant properties. CDF decreased PC cell survival, clonogenicity, formation of pancreatospheres, invasive cell migration and CSC function in human PC cells. These effects were associated with decreased expression of EZH2 and increased expression of a panel of tumor suppressive microRNAs (miRNAs), including let-7a,b,c,d, miR-26a, miR-101, miR-146a, and miR-200b,c that are typically lost in PC. Mechanistic investigations revealed that re-expression of miR-101 was sufficient to limit the expression of EZH2 and the pro- invasive cell surface adhesion molecule EpCAM. In an orthotopic xenograft model of human PC, 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 PC tumor growth and aggressiveness by targeting an EZH2-miRNA regulatory circuit for epigenetically controlled gene expression.
Cancer Research 2011