Fan Xuan

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10_PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10_PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10_PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10_PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10_PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10_PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10_PZP-dependent CALM-AF10-mediated leukemogenesis.

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by ‘reader’ proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia¹. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour^2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.

CDGSH iron sulfur domain 2 (CISD2) is reported to be highly expressed in several cancers, but the role of it in neuroblastoma has not been identified yet. Here, for the first time, we show that CISD2 is involved in neuroblastoma tumorigenesis and regulates neuroblastoma cell proliferation and differentiation. We found that high CISD2 expression correlated significantly with poor outcome of neuroblastoma patients, as well as advanced neuroblastoma tumor stages. Knockdown of CISD2 greatly repressed neuroblastoma cell proliferation and tumorigenesis both in vitro and in vivo. Further investigation showed that CISD2 deficiency resulted in cell cycle arrest in G1 phase and induced cell differentiation of neuroblastoma. Several Cyclins and Cyclin-Dependent Kinases (CDKs) were down-regulated by CISD2 knockdown, indicating that CISD2 probably regulates cell cycle through those genes. Together, we provide evidence that CISD2 is an indicator for neuroblastoma patients prognosis and is indispensable for neuroblastoma cell proliferation and tumorigenesis; CISD2 deficiency can induce neuroblastoma cell cycle arrest and differentiation. These findings suggest that CISD2 could work as a novel and potential therapeutic target for neuroblastoma treatment.

MYC-induced nuclear antigen (MINA53) is a JmjC (jumonji C domain)-containing protein, which is highly expressed in many cancers including glioblastoma. We have revealed in our previous report that MINA53 is a poor prognostic indicator for glioblastoma patients, and knockdown of MINA53 could reduce glioblastoma malignancy. In this study, we found that MINA53 knockdown could decrease the DNA replication initiation in glioblastoma cells. Through further investigations, we revealed that MINA53 could regulate the expression of the CDC45-MCM-GINS (CMG) complex genes, which are vital for DNA replication initiation. Knockdown of MINA53 reduced the CMG genes expression and thus induced DNA replication stress and DNA damage. Furthermore, MINA53 knockdown diminished DNA damage response (DDR) by reducing the ATM/ATR-H2AX pathway activity and finally led glioblastoma cells to apoptosis and death. We further applied a genotoxic drug Doxorubicin and found that MINA53 deficiency sensitized glioblastoma cells to Doxorubicin. Our study reveals that MINA53 is involved in DNA replication initiation and DNA damage response, and provides support for MINA53 as a novel and potential therapeutic target for glioblastoma treatment.

Oncogene is one of the world’s leading cancer journals. It is published weekly and covers all aspects of the structure and function of Oncogenes.

The transcription factor homeobox C9 (HOXC9) plays a crucial role in developmental regulatory systems, where it determines the specific positional identities of cells along the anteroposterior axis. The expression of HOXC9 has been found to be dysregulated in some cancers such as lung cancer, breast cancer, and neuroblastoma. Here, we report for the first time that HOXC9 is a novel autophagy regulator and reveal its oncogenic role in cell survival and its usefulness as a prognostic marker in glioblastoma patients. Kaplan-Meier analysis was performed to evaluate the possible prognostic value of HOXC9 in glioblastoma. Growth curve assays, subcutaneous, and orthotopic implantations were used to analyze cell viability and tumor formation, respectively. Luciferase and chromatin immunoprecipitation assays were employed to explore the mechanisms involved in the association between HOXC9 and its downstream effector, death-associated protein kinase 1 (DAPK1). High expression of HOXC9 was found to be an indicator of a poor prognosis in glioblastoma. HOXC9 knockdown resulted in a significant reduction of cell viability, migration, invasion, and tumorigenicity and a marked increase in autophagy. During the autophagy process, HOXC9 inhibited DAPK1 transcription by directly binding to its promoter. The downregulation of HOXC9 releases its transcriptional inhibition of DAPK1, resulting in the activation of the DAPK1-Beclin1 pathway, which induces autophagy in glioblastoma cells. Collectively, our data indicate that HOXC9 is an oncogene in glioblastoma. We have revealed its role in the control of autophagy, and we suggest that HOXC9 is a novel and promising therapeutic target.

RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration

Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β