Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes with features of high stability, tissue-specific and cell-specific expression. According to their biogenesis, circRNAs are mainly classified into five types, i.e. exonic circRNAs (EciRNAs), exon-intron circRNAs (EIciRNAs), intronic RNAs (CiRNAs), fusion circRNAs (f-circRNAs), and read-through circRNAs (rt-circRNAs). CircRNAs have been emerging as important non-coding regulatory RNAs in a variety of human cancers. CircRNA4s were revealed to exert regulatory function through multiple mechanisms, such as sponges/decoys of miRNAs and proteins, enhancers of protein functions, protein scaffolds, protein recruitment, or protein translation templates. Furthermore, some circRNAs are intensively associated with immune cells in tumor immune microenvironment (TIME), e.g. circARSP91 and natural killer cells. Through regulating immune checkpoint genes, circRNAs are demonstrated to modulate the immune checkpoint blockade immunotherapy, e.g. circCPA4 could up-regulate PD-L1 expression. In summary, we reviewed the molecular features of circRNAs and mechanisms how they exert functions. We further summarized functional implications of circRNA regulations in tumor immunology and immunotherapy. Further understanding of the regulatory roles of circRNAs in tumor immunology and immunotherapy will benefit tumor treatment.

Prostate cancer is among the top mortality factors in male around the world. Long non-coding RNAs (lncRNAs) have been shown to play crucial roles in tumor biology and immunology. However, lncRNA-immune interactions have not yet examined in prostate cancer. Here, we performed integrated analysis to characterize lncRNA-immune interactions in prostate cancer through multidimensional aspects, including immune-related hallmarks, tumor immunogenomic signatures, immune-related biological processes, immune cells, and immune checkpoints. We dissected the dysregulation of lncRNAs and their clinical relevance in prostate cancer, such as RP11-627G23.1 and RP11-465N4.5. Immune-related hallmarks took up the major parts among top significant lncRNA-hallmark interactions. Our analysis revealed that TGF-β signaling pathway was the most frequent to associate with lncRNAs, which is a signature of immune response in cancer. In addition, immune response and its regulation were the most closely connected immunological processes with lncRNA, implying the regulatory roles of lncRNAs on immune response in prostate cancer. We found that memory resting CD4+ T cells were the most lncRNA-correlated immune cell. LINC00861 was found to be potentially intervening targets of immunotherapy for prostate cancer patients, which was significantly associated with PD-1 and CTLA4. Collectively, we offered a handy resource to investigate regulatory roles of lncRNAs on tumor immunology and the development of clinical utility of lncRNAs in prostate cancer.