JHDM1B is an evolutionarily conserved and ubiquitously expressed member of the JHDM (JmjC-domain-containing histone demethylase) family. Because it contains an F-box motif, this protein is also known as FBXL10 (ref. 4). With the use of a genome-wide RNAi screen, the JHDM1B worm orthologue (T26A5.5) was identified as a gene that regulates growth. In the mouse, four independent screens have identified JHDM1B as a putative tumour suppressor by retroviral insertion analysis. Here we identify human JHDM1B as a nucleolar protein and show that JHDM1B preferentially binds the transcribed region of ribosomal DNA to repress the transcription of ribosomal RNA genes. We also show that repression of ribosomal RNA genes by JHDM1B is dependent on its JmjC domain, which is necessary for the specific demethylation of trimethylated lysine 4 on histone H3 in the nucleolus. In agreement with the notion that ribosomal RNA synthesis and cell growth are coupled processes, we show a JmjC-domain-dependent negative effect of JHDM1B on cell size and cell proliferation. Because aberrant ribosome biogenesis and the disruption of epigenetic control mechanisms contribute to cellular transformation, these results, together with the low levels of JHDM1B expression found in aggressive brain tumours, suggest a role for JHDM1B in cancer development.

The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes.

The introduction of immune checkpoint inhibitors in cancer treatment highlights the negative regulation of anti-tumor immunity, such as effector T-cell exhaustion in the tumor microenvironment. However, the mechanisms underlying the induction and prevention of T-cell exhaustion remain largely unknown. We found that CD69, a type II glycoprotein known to regulate inflammation through T-cell migration and retention in tissues, plays an important role in inducing the exhaustion of tumor-infiltrating T cells. Cd69-/- mice showed reduced tumor growth and metastasis in a 4T1-luc2 murine breast cancer model, in which increased numbers of tumor-infiltrating lymphocytes, relatively little T-cell exhaustion, and enhanced IFNγ production were observed. Anti-CD69 monoclonal antibody treatment attenuated the T-cell exhaustion and tumor progression in tumor-bearing mice. These findings highlight a novel role of CD69 in controlling the tumor immune escape mediated by T-cell exhaustion and indicate that CD69 is a novel target for cancer immunotherapy.

The F-box protein ␤Trcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-B family of transcription factors. Here we show that mammary glands of ␤Trcp1 ؊/؊ female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of ␤Trcp1 in mammary gland development, we generated transgenic mice expressing human ␤Trcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV ␤Trcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV ␤Trcp1 mice proliferate more and show increased NF-B DNA binding activity and higher levels of nuclear NF-B p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of ␤Trcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that ␤Trcp1 positively controls the proliferation of breast epithelium and indicate that alteration of ␤Trcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-B transactivation.F-box proteins (FBPs) are defined by the presence of an approximately 40-amino-acid domain named the F box after the protein, cyclin F, in which it was originally identified (2). Studies in different species have shown that FBPs play a crucial role in the ubiquitin-mediated degradation of cellular regulatory proteins (e.g., cyclins, cyclin-dependent kinase inhibitors, ␤-catenin, IB, etc.) (reviewed in references 11, 29, and 31). Indeed, FBPs are subunits of ubiquitin ligases named SCFs because they comprise Skp1, Cul1, and one of many FBPs.␤Trcp1 (␤-transducin repeat-containing protein), the mammalian ortholog of Xenopus ␤TrCP (53), was identified by using either Skp1 or the pseudosubstrate Vpu as bait in twohybrid screens (13,41). Mammalian ␤Trcp1 and the paralogous protein ␤Trcp2 have been reported to be involved in the degradation of IB (inhibitor of NF-B [nuclear factor B]) family members in response to NF-B-activating stimuli (17,21,24,25,32,45,49,52,(59)(60)(61). Several studies have reported that ␤Trcp1 and ␤Trcp2 also control ␤-catenin stability in mammalian cultured cells (23,24,30,37,43,59). Furthermore, additional ␤Trcp substrates have been proposed: Atf4/Creb2 (35), Smad3 (18), Smad4 (57), the alpha interferon receptor (33), the prolactin receptor (38), and the disks large tumor suppressor (40). More recently, ␤Trcp1 and ␤Trcp2 have been implicated in cell cycle control. During the S and G 2 phases, these two FBPs keep Cdk1 inactive by inducing the degradation of its activating phosphatase Cdc25a (9, 28). At the G 2 /M transition, ␤Trcp1 and ␤Trcp2 change their specificity by targeting the Cdk1-inactivating kinase Wee1 for degradation (58), resulting in Cdc25a accumula...

c-Jun is a component of the heterodimeric transcription factor AP-1 that is rapidly activated in response to ultraviolet light (UV). In unstressed cells, c-Jun activity is negatively regulated by transcriptional repressor complexes. Here we show that the F-box protein Fbl10/JHDM1B interacts with c-Jun and represses c-Jun-mediated transcription. Chromatin-immunoprecipitation assays demonstrate that Fbl10 is present at the c-jun promoter, and that c-Jun is required for the recruitment of Fbl10. Fbl10 binds to the unmethylated CpG sequences in the c-jun promoter through the CxxC zinc finger and tethers transcriptional repressor complexes. Suppression of Fbl10 expression by RNA interference (RNAi) induces transcription of c-jun and other c-Jun-target genes, and causes an aberrant cell-cycle progression and increased UV-induced cell death. Furthermore, Fbl10 protein and messenger RNA are downregulated in response to UV in an inverse correlation with c-Jun. Taken together, our results demonstrate that Fbl10 is a key regulator of c-Jun function.