Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase.

The linchpin of colorectal cancer is the oncoprotein and transcriptional cofactor β-catenin, whose overexpression is causative for the neoplastic transformation of colon cells. However, the molecular details of β-catenin dependent gene transcription in cancer cells are still not comprehensively explored. Here, we show that the histone demethylase KDM4B was upregulated in colon and rectal adenocarcinomas and required for efficient growth and clonogenic activity of human HT-29 colon cancer cells. Moreover, KDM4B formed complexes with β-catenin in vitro and in vivo, which involved its central amino acids 353-740. In addition, KDM4B also interacted with the DNA-binding protein TCF4, which is the main factor recruiting β-catenin to chromatin in the intestine. KDM4B downregulation resulted in reduced expression of the β-catenin/TCF4 target genes JUN, MYC and Cyclin D1, all of which encode for oncoproteins. Collectively, our data indicate that KDM4B overexpression supports β-catenin mediated gene transcription and thereby contributes to the genesis of colorectal tumors. Accordingly, inhibition of the KDM4B histone demethylase may represent a novel avenue of fighting colorectal cancer, one of the major causes of cancer death throughout the world.