JARID1B

Official Full Name

lysine demethylase 5B

Organism

Homo sapiens

GeneID

10765

Background

This gene encodes a lysine-specific histone demethylase that belongs to the jumonji/ARID domain-containing family of histone demethylases. The encoded protein is capable of demethylating tri-, di- and monomethylated lysine 4 of histone H3. This protein plays a role in the transcriptional repression or certain tumor suppressor genes and is upregulated in certain cancer cells. This protein may also play a role in genome stability and DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

Synonyms

KDM5B; CT31; PLU1; PUT1; MRT65; PLU-1; JARID1B; PPP1R98; RBP2-H1; RBBP2H1A;

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Detailed Information

Recent Research Progress

JARID1B, known as PLU1 or KDM5B, is a histone demethylase. In fact, some reports show that it converts tri- and dimethylated lysine 4 in histone H3 (H3K4me3/2) to the monomethylated form (H3K4me1). JARID1B is the member of the JARID1 protein family, which also includes JARID1A/RBP2/KDM5A, JARID1C/SMCX/ KDM5C, and JARID1D/SMCY/KDM5D. In fact, JARID1B contains three potential consensus TRAF6 binding motifs (PxExxAr/Ac), which are adjacent to the ubiquitination site of JARID1B at lysine 242. In addition, JARID1B has been reported to be highly expressed in various human cancers.JARID1Bwas first identified as a gene whose expression was reversibly regulated by HER2 signaling in breast cancer cells. It is the first time that JARID1B affects female fertility. Moreover, JARID1B/KDM5B is a key component of the epigenetic mechanisms that control Runx2 expression during osteoblast and myoblast differentiation. JARID1B is often mutated in breast tumors and that it regulates luminal and basal cell-specific expression programs. Some reports show that JARID1B is a luminal lineage-driving oncogene that may represent a target in luminal breast tumors.

Overexpression of JARID1B leads to the gain of unique chromatin binding and luminal expression and splicing patterns. Down regulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGF pathway inhibitors. Some researchers report that overexpression of JARID1B in HeLa cells results in loss of tri-, di-, and monomethyl H3K4 but do not affect H3K9, H3K27, or H3K36 methylation. Overexpression of JARID1B in prostate carcinomas associates with the androgen receptor and regulates its transcriptional activity. Tumor growth-promoting effects of JARID1B have also been described in bladder and lung cancers. In contrast, the downregulation of JARID1B has been implicated as a tumor suppressor inhibiting cell proliferation in an RB-dependent manner. Overexpression in ESCs decreases the expression of differentiated cell-specific genes and increases proliferation. Overexpression of JARID1B is associated with poor prognosis and chemotherapy resistance in epithelial ovarian cancer. The downregulation of JARID1B did not affect the protein levels of the closely related JARID1A, and it only slightly increased global histone H3K4me3 levels in the MCF7 and T-47D luminal breast cancer cell lines. Knockdown of JARID1B reduced the tumor formation potential of MCF-7 luminal breast cancer cells. JARID1B loss induced a decrease rather than an increase in H3K4me3 levels at many of its target promoters. JARID1B loss correlated negatively with up-regulated genes in luminal cells as well as down-regulated genes in MaSC-enriched cells. Loss of Jarid1b leads to reduced serum estrogen level and decreased proliferation of mammary epithelial cells. JARID1B is regulated by SKP2 through K63-linked ubiquitination. An increase of JARID1B ubiquitination in the absence of SKP2 will competitively decrease the free lysine 242 for the sumoylation-mediated degradation by RNF4. Loss of JARID1B inhibits breast cancer cell growth. JARID1B loss leads to decreased TGF pathway activity, but this may not play a role in JARID1B loss mediated growth arrest in this cell type.

High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor-positive breast tumors. JARID1B is a target of the 1q32 amplicon and suggested that JARID1B function might particularly be important in ER+ luminal breast cancer cells. JARID1B expression in luminal breast cancer cells is required for the repression of basal cell-specific genes, including those important for TGF signaling, and the loss of this repression following decreased JARID1B leads to growth arrest. JARID1B maintains proper levels of ER-dependent transcription in the mammary gland and ensures timely lineage differentiation of epithelial cells (Fig.1).

Figure 1. Proposed model for JARID1B regulation of mammary gland development and female fertility through both endocrine and cell-autonomous.

In addition to its demethylase function, JARID1B can form a complex with HDAC4 and LSD1/NuRD to mediate transcriptional repression. Its known repressed target genes in breast cancer include BRCA1, CAV1, and CCL4. Therefore, JARID1B may be more potent chemotherapy for CRPC treatment. JARID1B facilitated GATA3 recruitment to the promoter of genes involved in mammary development and activated their transcription. JARID1B could serve as an important biomarker for prognosis and chemotherapy resistance of EOC patients. JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms. Some study revealed a novel function of SKP2 in mediating JARID1B for histone methylations (Figure 2).

Figure 2. SKP2 positively correlates with H3K4me3 in human prostate cancer specimens.

References:

Yamamoto S, et al.JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell, 2014, 25(6):762-777.
Lu W, et al. SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget, 2015, 6(2):771-88.
Lin C S, et al. Silencing JARID1B suppresses oncogenicity, stemness and increases radiation sensitivity in human oral carcinoma. Cancer Letters, 2015, 368(1):36-45.
Zou M R, et al. Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) controls mammary gland development by regulating key developmental and lineage specification genes. Journal of Biological Chemistry, 2014, 289(25):17620.
Wang L, et al. Overexpression of JARID1B is associated with poor prognosis and chemotherapy resistance in epithelial ovarian cancer. Tumor Biology, 2015, 36(4):2465-2472.

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