PLU-1 Is an H3K4 Demethylase Involved in Transcriptional Repression and Breast Cancer Cell Proliferation

Abstract

Posttranslational modification of chromatin by histone methylation has wide-ranging effects on nuclear function, including transcriptional regulation, maintenance of genome integrity, and epigenetic inheritance. The enzymes utilized to place histone methylation marks are well characterized, but the identity of a histone demethylation system remained elusive until recently. The discovery of histone demethylase enzymes capable of directly removing methyl groups from modified lysine residues has demonstrated that histone methylation is a dynamic modification. The most extensive family of histone demethylase enzymes identified so far contains a JmjC domain and catalyzes demethylation through a hydroxylation reaction. Here, we identify PLU-1, a transcriptional repressor implicated in breast cancer, as a histone demethylase enzyme that has the ability to reverse the trimethyl H3K4 modification state. Furthermore, we reveal that PLU-1-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1.

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

“…A reasonable explanation for the discrepancy could be that the main part of the detected RBP2-H1-DNA interactions is not directly involved into transcriptional regulation of the corresponding genes, but rather affects other mechanisms of nuclear homeostasis, such as regulation of chromatin structure via histone methylation, as it has been recently suggested for PLU-1/JARID1B and RBP2/JARID1A. 6,7,11,65,66 Posttranslational modification of chromatin by histone methylation has wide-ranging effects on nuclear function, including maintenance of genome integrity, epigenetic inheritance and, of course, transcriptional regulation. 6 Thereby, the regulated genes do not necessarily have to be located in close relationship up-or downstream to the regulatory chromosomal element.…”

“…3 PHD motifs and the ARID (AT-rich interacting) DNA-binding domain. [6][7][8][9] Although the 3 splicing variants show a cDNA sequence homology of more than 98%, RBP2-H1 differs from PLU-1 and RBBP2H1a by an additional exon encoding a region with strong homology to chromosomal ALU repeats. Thus, previously reported differences in tissue expression (PLU-1 shows a restricted expression in most normal tissues and a marked upregulation in breast cancer) or possible variations in protein function of RBP2-H1 and PLU-1 would be explicable.…”

T cells reactive with HLA‐A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients

“…However, only JARID1B has been reported to be expressed in cancer. 7,9,11,14 JARID1A shows a wider range of expression, and JARID1C is associated with neural development and X-linked mental retardation. 37 The JARID1B HLA-A*0201 epitopes analyzed here were selected for showing the least conservation between the other JARID1 proteins, and any T cells generated should not react with the other members of the JARID1 family.…”

“…Effects of modulating the expression of JARID1B on the cell cycle, and on genes related to proliferation have identified diverse responses, depending on the cell type. 12,14,16 In primary breast cancers, JARID1B is preferentially expressed in ER þ cancers (data obtained from www.oncomine.org/), and work with ER þ MCF-7 cells and RNAi KO shows that expression of the protein enhances the growth of these cells in vitro and in nude mice (Catchpole et al PLoS One-under review).…”

“…The presence of the ARID (AT Rich DNA binding domain) and JmjN and JmjC domains places JARID1B, along with 3 other highly homologous proteins in the JARID1 subgroup of ARID proteins 13,14 (Supporting Information Figure 1) The identification of the JmjC related H3K4me3 demethylase activity led to the KDM5B (histone demethylase) classification, 12,15 but the JARID1 nomenclature is most widely used-the demethylase activity being only one of the functions of these proteins. Among the four JARID1 proteins, only PLU-1/JARID1B (hereafter referred to as JARID1B) was The scores are an average from two independent assessors.…”