Biological Function Of Histone Demethylase JMJD2D In Colorectal Cancer Progression

Epigenetic modification can promote cancer development through activating oncogenes or downregulating the expression of tumor suppressors.The histone demethylase JMJD2D(lysine demethylase 4D,KDM4D)belongs to the containing Jmjc domain histone demethylases JMJD2 family,which has other three members JMJD2A(KDM4A),JMJD2B(KDM4B)and JMJD2C(JMJD2C).JMJD2D induces gene expression by removing the methyl group from H3K9me3 and H3K9me2.Although it has been reported that JMJD2D could activate androgen receptor,promote DNA damage repair and initiate DNA replication,its roles in cancer development remain unclear.Just a case reported that down-regulation of JMJD2D can inhibit HCT116 cells proliferation,however,there was no clear study on whether it promotes colorectal cancer development and the specific mechanism of how it works.Our previous study found that:①65.2%(30/46)of colorectal cancer samples showed high expression of JMJD2D compared with non-tumor tissues,and its expression was positively correlated with the expression of tumor proliferation marker PCNA;②downregulation of JMJD2D could significantly inhibit the proliferation,migration and invasion of human colorectal cancer HCT116 and SW480 cells.Based on these studies,the purpose of this study is to explore the role of JMJD2D in colorectal cancer development and its specific molecular mechanisms.Further research results show that:①JMJD2D can also inhibit the proliferation,migration and invasion in the mice colorectal cancer CT26 cells;②downregulation of JMJD2D reduces the subcutaneous tumorigenesis,lung metastasis and liver metastasis ability of colorectal cancer cells;③JMJD2D upregulates beta-catenin and interactes with beta-catenin to enhance the transcriptional activity of the Wnt target gene,activating the Wnt/beta-catenin pathway;④ JMJD2D interacts with HIF1α to enhance glycolysis;⑤ JMJD2D knockout prevents colorectal cancer development;⑥inhibition of JMJD2D can prevent the colorectal cancer cells growth,tumorigenesis and colorectal cancer development.In a word,we conclude that JMJD2D promotes colorectal cancer development by enhancing Wnt/beta-catenin and HIF1α pathway;inhibition of JMJD2D can inhibit colorectal cancer development.Our study provides a theoretical evidence for JMJD2D acting as a potential target as well as a candidate drug for the treatment of colorectal cancer.