ZNF498 promotes hepatocellular carcinogenesis by suppressing p53-mediated apoptosis and ferroptosis via the attenuation of p53 Ser46 phosphorylation.

BACKGROUND: Dysfunctional p53 signaling is one of the major causes of hepatocellular carcinoma (HCC) tumorigenesis and development, but the mechanisms underlying p53 inactivation in HCC have not been fully clarified. The role of Krüppel-associated box (KRAB)-type zinc-finger protein ZNF498 in tumorigenesis and the underlying mechanisms are poorly understood. METHODS: Clinical HCC samples were used to assess the association of ZNF498 expression with clinicopathological characteristics and patient outcomes. A mouse model in which HCC was induced by diethylnitrosamine (DEN) was used to explore the role of ZNF498 in HCC initiation and progression. ZNF498 overexpression and knockdown HCC cell lines were employed to examine the effects of ZNF498 on cellular proliferation, apoptosis, ferroptosis and tumor growth. Western blotting, immunoprecipitation, qPCR, luciferase assays and flow cytometry were also conducted to determine the underlying mechanisms related to ZNF498 function. RESULTS: ZNF498 was found to be highly expressed in HCC, and increased ZNF498 expression was positively correlated with advanced pathological grade and poor survival in HCC patients. Furthermore, ZNF498 promoted DEN-induced hepatocarcinogenesis and progression in mice. Mechanistically, ZNF498 directly interacted with p53 and suppressed p53 transcriptional activation by inhibiting p53 Ser46 phosphorylation. ZNF498 competed with p53INP1 for p53 binding and suppressed PKCδ- and p53INP1-mediated p53 Ser46 phosphorylation. In addition, functional assays revealed that ZNF498 promoted liver cancer cell growth in vivo and in vitro in a p53-dependent manner. Moreover, ZNF498 inhibited p53-mediated apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation. CONCLUSIONS: Our results strongly suggest that ZNF498 suppresses apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation in hepatocellular carcinogenesis, revealing a novel ZNF498-PKCδ-p53INP1-p53 axis in HCC cells that would enrich the non-mutation p53-inactivating mechanisms in HCC.

Evidence for the Superatom-Superatom Bonding from Bond Energies.

Metal clusters with specific number of valence electrons are described as superatoms. Super valence bond (SVB) model points out that superatoms could form the superatomic molecules through SVBs by sharing nucleus and electrons. The existence of superatom-superatom bonding was verified by the shape of their orbitals in former studies. In this paper, another important evidence-bond energy is studied as the criterion for the SVBs using the density functional theory method. In order to get the reliable values of bond energies, the series of Zn-Cu and Mg-Li superatomic molecules composed of two tetrahedral superatoms which do not share their nucleus are designed. Considering the number of the valence electrons in one tetrahedral superatomic unit, (Zn4)2/(Mg4)2, (Zn3Cu)2/(Mg3Li)2, (Zn2Cu2)2/(Mg2Li2)2, and (ZnCu3)2/(MgLi3)2 clusters are 8e-8e, 7e-7e, 6e-6e, and 5e-5e binary superatomic molecules with super nonbond, single bond, double bond, and triple bond, respectively, which are verified by chemical bonding analysis depending on the SVB model. Further calculations reveal that the bond energies increase and the bond lengths decrease along with the bond orders in Zn-Cu and Mg-Li systems which is in accordance with the classical nonbond, single bond, double bond, and triple bond in C-H systems. Thus, these values of bond energies confirm the existence of the SVBs. Moreover, electron localization function analysis is also carried on to describe the similarity between the superatomic bonds and atomic bonds in simple molecules directly. This study reveals the new evidence for the existence of the superatom-superatom bonding depending on the bond energies, which gives the new insight for the further investigation of the superatomic clusters.

Genetic Structure and Evolutionary History of Three Alpine Sclerophyllous Oaks in East Himalaya-Hengduan Mountains and Adjacent Regions.

The East Himalaya-Hengduan Mountains (EH-HM) region has a high biodiversity and harbors numerous endemic alpine plants. This is probably the result of combined orographic and climate oscillations occurring since late Tertiary. Here, we determined the genetic structure and evolutionary history of alpine oak species (including Quercus spinosa, Quercus aquifolioides, and Quercus rehderiana) using both cytoplasmic-nuclear markers and ecological niche models (ENMs), and elucidated the impacts of climate oscillations and environmental heterogeneity on their population demography. Our results indicate there were mixed genetic structure and asymmetric contemporary gene flow within them. The ENMs revealed a similar demographic history for the three species expanded their ranges from the last interglacial (LIG) to the last glacial maximum (LGM), which was consistent with effective population sizes changes. Effects of genetic drift and fragmentation of habitats were responsible for the high differentiation and the lack of phylogeographic structure. Our results support that geological and climatic factors since Miocene triggered the differentiation, evolutionary origin and range shifts of the three oak species in the studied area and also emphasize that a multidisciplinary approach combining molecular markers, ENMs and population genetics can yield deep insights into diversification and evolutionary dynamics of species.