Department of Cell Biology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73104, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Columbus, OH 43210, USA.
Am J Transl Res. 2014 May 15;6(3):236-47. eCollection 2014.
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.
结肠肿瘤是癌症死亡的主要原因，但它们的分子复杂性尚未完全被理解。我们证明组蛋白去甲基酶 JMJD2A、JMJD2B 和 JMJD2C 在结肠癌细胞系中过度表达，而另一种相关蛋白 JMJD2D 则没有。有趣的是，尽管它们具有高度同源性，但 JMJD2A-C 在结肠和其他癌细胞中的细胞内定位不同，JMJD2A 在细胞质和细胞核中存在的比例相当，JMJD2B 更倾向于细胞核，而 JMJD2C 则与染色质强烈相关。这表明这三种蛋白质中的每一种都具有不同的、非冗余的功能。此外，我们表明 JMJD2C（也称为 KDM4C）与β-连环蛋白形成复合物，β-连环蛋白是一种癌蛋白，其过度表达对大多数结肠肿瘤的发展至关重要。此外，JMJD2C 的下调降低了 HCT-116 结肠癌细胞的生长和集落形成能力。此外，JMJD2C 是生长刺激蛋白 FRA1 和细胞周期蛋白 D1 以及生存因子 BCL2 的有效表达所必需的。最后，我们鉴定出姜黄素的衍生物是 JMJD2 酶的体外抑制剂，这表明这些姜黄素类化合物可用于降低体内 JMJD2 活性。总之，我们的数据强调了 JMJD2C 的过度表达赋予结肠癌细胞促生长作用，因此，其抑制作用通过姜黄素类化合物或其他小分子作为结肠癌患者的辅助治疗可能是有益的。
