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

Abstract

Abstract. 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. IntroductionColorectal cancer is a major health issue and over 50,000 US residents alone are expected to die from this disease this year (1). A crucial defect in the vast majority of colorectal tumors is the overexpression of the oncoprotein β-catenin. This is primarily due to the loss of the tumor suppressor adenomatous polyposis coli (APC), which normally directs the intracellular destruction of β-catenin, or activating mutations in β-catenin itself (2). Unfortunately, knowledge on the devastating impact of these genetic mutations has not yet translated into improved therapy.Aside from genetic mutations, epigenetic changes are an underlying cause of tumorigenesis. Most prominently, such epigenetic changes involve the methylation of DNA on cytosine residues and the modification of histones by acetylation and methylation (3,4). In contrast to DNA methylation and histone acetylation, the methylation of histones was only recently validated as a major epigenetic mechanism. Methylation occurs on lysine and arginine residues at multiple sites on histones and the tight regulation of the histone methylation status is absolutely required for normal cell physiology and safeguards against aberrant cell growth. Thus, enzymes affecting histone methylation play seminal roles in cellular homeostasis and, accordingly, dysregulation of both histone methyltransferases as well as the opposing demethylases is thought to be capable of inducing cancer (5,6). However, the roles of the enzymes determining histone methylation in colorectal tumors are largely unexplored.The family of human Jumonji C domain containing proteins comprises 30 members, many of which have been shown to function as histone demethylases (7). These include the four related lysine-specific demethylase 4 (KDM4) proteins...

Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β‐catenin pathway in mice

“…Our previous investigations (20) have illustrated that although Brg1 interacts with several members of the H3K4 trimethyl transferase complex COMPASS to regulate endothelin transcription in the pathogenesis of cardiac hypertrophy, Brg1 also cooperates with the histone acetyltransferase p300 to regulate profibrogenic transcription, promoting renal fibrosis (28). In agreement with our discoveries, several independent studies suggest that Kdm4 promotes carcinogenesis at least in part by activating the Wnt/b-catenin pathway (29,30). What remains to be addressed is how that Brg1-Kdm4 interaction regulates liver injury by contributing to the genome-wide chromatin revamping.…”

Distinct Biochemical and Functional Properties of Two Rab5 Homologs from the Rice Blast Fungus Magnaporthe oryzae

“…Virus production and infection of cells was performed similarly as reported (27). Briefly, lentiviruses were generated by co-transfecting the 3rd generation packaging plasmids pMD2.G (addgene), pMDL/RRE g/p (addgene), and pRSV-Rev (addgene) along with the lentiviral expression constructs into human embryonic kidney 293T cells using the polyethylenimine transfection method.…”

PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway

“…The constitutively active canonical Wnt/β-catenin signaling pathway has been documented in MM. However, MM remains incurable because of drug resistance, relapse or refractory (28)(29)(30). Therefore, further exploration of novel and more selective molecular targets is necessary.…”

“…Nuclear localization of the β-catenin is translocated from the cytoplasm into the nucleus to stimulate Wnt/β-catenin signaling and then to accelerate tumor cell proliferation (27,30). Since we have confirmed that PCDH10 suppresses MM cell growth by targeting Wnt signaling, we investigated whether the functional PCDH10 disturbed the nuclear translocation of β-catenin and its coactivator BCL-9.…”

“…The Wnt/β-catenin pathway is frequently activated in various types of cancer and is involved in cancer cell proliferation, survival and invasion (29,30). To determine whether the inhibitory effect of PCDH10 is connected with Wnt signaling, a luciferase assay was utilized to detect the Wnt activity in MM cells transfected with or without PCDH10.…”