Deltex E3 ubiquitin ligase 3 inhibits colorectal cancer cell growth and regulates cell cycle progression via upregulating E2F transcription factor 1

Molecular Biology Reports - The mortality rate of colorectal cancer (CRC) remains high in developing countries. Interventions that can inhibit the proliferation of tumor cells represent promising...     

PCLAF promotes neuroblastoma G1/S cell cycle progression via the E2F1/PTTG1 axis

PCLAF (PCNA clamp-associated factor), also known as PAF15/ KIAA0101, is overexpressed in most human cancers and is a predominant regulator of tumor progression. However, its biological function in neuroblastoma remains unclear. PCLAF is extremely overexpressed in neuroblastoma and is associated with poor prognosis. Through the analysis of various data sets, we found that the high expression of PCLAF is positively correlated with increased stage and high risk of neuroblastoma. Most importantly, knocking down PCLAF could restrict the proliferation of neuroblastoma cells in vitro and in vitro. By analyzing RNA-seq data, we found that the enrichment of cell cycle-related pathway genes was most significant among the differentially expressed downregulated genes after reducing the expression of PCLAF. In addition, PCLAF accelerated the G1/S transition of the neuroblastoma cell cycle by activating the E2F1/PTTG1 signaling pathway. In this study, we reveal the mechanism by which PCLAF facilitates cell cycle progression and recommend that the PCLAF/E2F1/PTTG1 axis is a therapeutic target in neuroblastoma.Subject terms: Cancer epigenetics, Cell growth     

BAP1 regulates cell cycle progression through E2F1 target genes and mediates transcriptional silencing via H2A monoubiquitination in uveal melanoma cells

Uveal melanoma (UM) is the most common form of primary intraocular malignancy in adult and has the tendency to metastasize. BAP1 mutations are frequently found in UM and are associated with a poor prognosis. The role of BAP1 in cell cycle regulation is currently a research highlight, but its underlying mechanism is not well understood. Here, we report that BAP1 knockdown can lead to G1 arrest and is accompanied by a decrease in the expression of S phase genes in OCM1 cells. Furthermore, in chromatin immunoprecipitation experiments, BAP1 could bind to E2F1 responsive promoters and the localization of BAP1 to E2F1-responsive promoters is host cell factor-1 dependent. Moreover, BAP1 knockdown leads to increased H2AK119ub1 levels on E2F responsive promoters. Together, these results provide new insight into the mechanisms of BAP1 in cell cycle regulation.     

Dominant negative E2F inhibits progression of the cell cycle after the midblastula transition in Xenopus

The cleavage cycle, which is initiated by fertilization, consists of only S and M phases, and the gap phases (G1 and G2) appear after the midblastula transition (MBT) in the African clawed frog, Xenopus laevis. During early development in Xenopus, we examined the E2F activity, which controls transition from the G1 to S phase in the somatic cell cycle. Gel retardation and transactivation assays revealed that, although the E2F protein was constantly present throughout early development, the E2F transactivation activity was induced in a stage-specific manner, that is, low before MBT and rapidly increased after MBT. Introduction of the recombinant dominant negative E2F (dnE2F), but not the control, protein into the 2-cell stage embryos specifically suppressed E2F activation after MBT. Cells in dnE2F-injected embryos appeared normal before MBT, but ceased to proliferate and eventually died at the gastrula. These cells contained decreased cdk activity with enhanced inhibitory phosphorylation of Cdc2 at Tyr15. Thus, E2F activity is required for cell cycle progression and cell viability after MBT, but not essential for MBT transition and developmental progression during the cleavage stage.     

Alien inhibits E2F1 gene expression and cell proliferation

Recently, using a proteomic approach we have identified the corepressor Alien as a novel interacting factor of the cell cycle regulator E2F1. Unclear was whether this interaction influences cell proliferation and endogenous E2F1 target gene expression. Here, we show by chromatin immunoprecipitation (ChIP) that Alien is recruited in vivo to the E2F binding sites present in the E2F1 gene promoter, inhibits the transactivation of E2F1 and represses endogenous E2F1 gene expression. Interestingly, using synchronized cells to assess the expression of Alien profile during cell cycle the levels of endogenous Alien are increased during G1, G1/S and G2 phase. Furthermore, stable transfection of Alien leads to reduction of cell proliferation. Thus, the data suggest that Alien acts as a corepressor for E2F1 and is involved in cell cycle regulation.