title: Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors.
abstract: Colon tumors are a major cause of cancer death, yet their molecular intricacies are not fully understood. We demonstrate that the histone demethylases JMJD2A, JMJD2B and JMJD2C are overexpressed in colon cancer cell lines, whereas another related protein, JMJD2D, is not. Interestingly, despite their high homology, the intracellular localization of JMJD2A-C is different in colon and other cancer cells, with JMJD2A being present comparably in the cytoplasm and nucleus, JMJD2B more prevalent in the nucleus and JMJD2C strongly associated with chromatin. This suggests that each of these three proteins performs different, non-redundant functions. Moreover, we show that JMJD2C (also called KDM4C) forms complexes with β-catenin, an oncoprotein whose overexpression is crucial for the development of most colonic tumors. In addition, JMJD2C downregulation reduced both growth and clonogenic capacity of HCT-116 colon cancer cells. Further, JMJD2C was required for efficient expression of the growth stimulatory proteins FRA1 and cyclin D1 as well as the survival factor BCL2. Lastly, we identified derivatives of curcumin as in vitro inhibitors of JMJD2 enzymes, suggesting that these curcuminoids could be useful for decreasing JMJD2 activity in vivo. In conclusion, our data highlight that overexpression of JMJD2C confers a pro-growth effect on colon cancer cells and, therefore, its inhibition by curcuminoids or other small molecules could be beneficial as an adjuvant therapy for colon cancer patients.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73104, USA.
authors.forename: Tae-Dong
authors.initials: TD
authors.lastname: Kim
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Schwartz
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Abdelhamid
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Etter
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73104, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center Oklahoma City, OK 73104, USA ; Peggy and Charles Stephenson Cancer Center Oklahoma City, OK 73104, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73104, USA ; Peggy and Charles Stephenson Cancer Center Oklahoma City, OK 73104, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
keywords: JMJD2C; KDM4C; colon cancer; curcumin; histone demethylase; β-catenin