Jun Chen

The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment.

Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are processed by the ribonuclease Dicer from distinct precursors, double-stranded RNA (dsRNA) and hairpin RNAs, respectively, although either may guide RNA silencing via a similar complex. The siRNA pathway is antiviral, whereas an emerging role for miRNAs is in the control of development. Here, we describe a virulence factor encoded by turnip yellow mosaic virus, p69, which suppresses the siRNA pathway but promotes the miRNA pathway in Arabidopsis thaliana. p69 suppression of the siRNA pathway is upstream of dsRNA and is as effective as genetic mutations in A. thaliana genes involved in dsRNA production. Possibly as a consequence of p69 suppression, p69-expressing plants contained elevated levels of a Dicer mRNA and of miRNAs as well as a correspondingly enhanced miRNA-guided cleavage of two host mRNAs. Because p69-expressing plants exhibited disease-like symptoms in the absence of viral infection, our findings suggest a novel mechanism for viral virulence by promoting the miRNA-guided inhibition of host gene expression.

Histone deacetylase (HDAC) inhibitors such as the phenyl hydroxamic acid PCI-24781 have emerged recently as a class of therapeutic agents for the treatment of cancer. Recent data showing synergy of HDAC inhibitors with ionizing radiation and other DNA-damaging agents have suggested that HDAC inhibitors may act, in part, by inhibiting DNA repair. Here we present evidence that HDAC enzymes are important for homologous recombinational repair of DNA double-strand breaks. Combination studies of PCI-24781 with the poly(ADP-ribose) polymerase inhibitor PJ34, an agent thought to produce lesions repaired by homologous recombination (HR), resulted in a synergistic effect on apoptosis. Immunofluorescence analysis demonstrated that HDAC inhibition caused a complete inhibition of subnuclear repair foci in response to ionizing radiation. Mechanistic investigations revealed that inhibition of HDAC enzymes by PCI-24781 led to a significant reduction in the transcription of genes specifically associated with HR, including RAD51. RAD51 protein levels were significantly decreased after 24 h of drug exposure both in vitro and in vivo. Consistent with inhibition of HR, treatment with PCI-24781 resulted in a decreased ability to perform homology directed repair of I-SceI-induced chromosome breaks in transfected CHO cells. In addition, an enhancement of cell killing was observed in Ku mutant cells lacking functional nonhomologous end joining compared with WT cells. Together these results demonstrate that HDAC enzymes are critically important to enable functional HR by controlling the expression of HR-related genes and promoting the proper assembly of HR-directed subnuclear foci.

Transcription factor p53 forms a network with associated factors to regulate the cell cycle and apoptosis in response to environmental stresses. However, there is currently no direct genetic evidence to show if or how the p53 pathway functions during organogenesis. Here we present evidence to show that the zebrafish def (digestive-organ expansion factor) gene encodes a novel pan-endoderm-specific factor. A loss-of-function mutation in def confers hypoplastic digestive organs and selectively up-regulates the expression of Delta113p53, counterpart to a newly identified isoform of p53 produced by an alternative internal promoter in intron 4 of the p53 gene in human. The increased Delta113p53 expression is limited to within the mutant digestive organs, and this increase selectively induces the expression of p53-responsive genes to trigger the arrest of the cell cycle but not apoptosis, resulting in compromised organ growth in the mutant. Our data demonstrate that, while induction of expression of p53 and/or its isoforms is crucial to suppress abnormal cell growth, Delta113p53 is tightly regulated by an organ/tissue-specific factor Def, especially during organogenesis, to prevent adverse inhibition of organ/tissue growth.