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2014 ; 6
(3
): 236-47
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Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells
and identification of curcuminoids as JMJD2 inhibitors
#MMPMID24936217
Kim TD
; Fuchs JR
; Schwartz E
; Abdelhamid D
; Etter J
; Berry WL
; Li C
; Ihnat MA
; Li PK
; Janknecht R
Am J Transl Res
2014[]; 6
(3
): 236-47
PMID24936217
show ga
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
?-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.