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Simple Summary: Immune checkpoint inhibitors are used in combination with other drugs as the first-line therapy in the treatment of metastatic renal cell carcinoma. Although these cancer immunotherapies have demonstrated high therapeutic efficacy, half of patients develop treatment resistance. In this study, we investigated the enhancement of the antitumor effect of immunosuppressants by a histone deacetylase (HDAC) inhibitor. A novel HDAC inhibitor, OBP-801, upregulated LMP2, an immunoproteasome subunit, in clear cell renal cell carcinoma (ccRCC) cells, resulting in enhanced MHC class I expression, and a combined treatment of OBP-801 and anti-PD-1 antibody effectively alleviated ccRCC in mice. Our results suggest that manipulating LMP2 expression using OBP-801 may have therapeutic implications for enhancing MHC class I presentation and improving the anti-tumor immune response in ccRCC. In particular, the combination of OBP-801 with anti-PD-1 antibody appears to be promising for ccRCC treatment. Background: Histone deacetylase (HDAC) inhibitors have been reported to exhibit immunomodulatory activities, including the upregulation of major histocompatibility complex class I (MHC class I). Although the immunoproteasome plays a pivotal role in MHC class I antigen presentation, its effect on immunotherapy for clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: This study assessed whether OBP-801, a novel HDAC inhibitor, affects the expression of immunoproteasome subunits and subsequently the MHC class-I-mediated anti-cancer immunity in ccRCC. We analyzed the data of 531 patients with ccRCC from the Cancer Genome Atlas Kidney Clear Cell Carcinoma database. We further evaluated the treatment efficacy of the combination of OBP-801 and anti-PD-1 in a ccRCC mouse model. Results: Low molecular mass polypeptide (LMP) 2 was correlated most positively with CD3E, CD8A, and CD8B expression and estimated CD8+ T cell number. In vitro studies showed that OBP-801 upregulated MHC class I presentation by inducing LMP2 expression in the ccRCC cell lines RENCA, 786-O, and Caki-1. In vivo studies in a syngeneic mouse model with subcutaneous implantation of RENCA cells showed that OBP-801 treatment increased the percentage of CD45+CD3e+ T cells in tumor-infiltrating lymphocytes. The combination of anti-PD-1 antibody and OBP-801 enhanced the anti-tumor effect, LMP2 protein expression, and MHC class I presentation in tumor cells. MHC class I presentation in the tumors of each mouse was positively correlated with the percentage of CD45+CD3e+ T cells. Conclusions: Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC. [ABSTRACT FROM AUTHOR]

In most human malignant tumors, retinoblastoma tumor-suppressor gene ( RB) product is inactivated by phosphorylation. Therefore, cancer preventive agents or molecular-targeting agents can inhibit the tumor growth at G1 phase through RB reactivation. However, little is known about the effectiveness of RB reactivating agents against malignancies with mutated RB. We report here that chemopreventive agent flavone, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also induce G1 phase arrest in malignant tumor cells with mutated RB. In human prostate cancer DU145 cells with mutated RB, flavone increased cyclin-dependent kinase ( CDK) inhibitors p21 and p27, and reduced cdk4 and cdk6, resulting in decrement of phosphorylated RB family proteins p130 and p107. LY294002 also dephosphorylated p107 and p130 proteins, whereas TSA dephosphorylated p130, but not p107. Furthermore, flavone induced G1 phase arrest in both mouse embryo fibroblast ( MEF) wild-type and MEF RB −/ − cells, but did not do so in RB, p107, and p130 triple-knockout MEF cells. These results suggested that p130 and p107 contributed to G1 phase arrest by flavone in RB-mutated cells. However, flavone induced tumor suppressor micro RNA miR-34a with reduction of E2F1 and E2F3, known to be downregulated by miR-34a, raising the possibility that miR-34a might partially contribute to G1 arrest by flavone. These results raise the possibility that RB reactivating chemopreventive agents or molecular targeting agents might also be effective against a variety of malignant tumor cells with mutant RB. [ABSTRACT FROM AUTHOR]

Abstract: p15INK4b functions as a tumor suppressor and implicated in cellular senescence. Here, we show that the Oct-1 binding site in the human p15INK4b gene promoter functions as a silencer. Oct-1 specifically interacts with this binding site in vitro and in vivo and SMRT and HDAC1 are present in the p15INK4b proximal promoter region. Moreover, mouse embryo fibroblasts (MEFs) lacking Oct-1 have shown significantly increased levels of p15INK4b protein compared to their normal counterparts. Treatment with a histone deacetylase (HDAC) inhibitor has activated the expression of p15INK4b in wild-type MEFs but has no effect in MEFs lacking Oct-1, suggesting that Oct-1 represses p15INK4b gene expression in an HDAC-dependent manner. Finally, we show that the expression of Oct-1 protein significantly decreases, whereas p15INK4b protein significantly increases with the cellular aging process. Taken together, these results suggest that Oct-1 is an important transcriptional repressor for p15INK4b gene and the transcriptional repression of the p15INK4b gene by Oct-1 may be one of the regulatory mechanisms of cellular senescence. [Copyright &y& Elsevier]

Purpose: Myxofibrosarcoma is characterized by a high rate of recurrence after surgery. Since myxofibrosarcoma is refractory to conventional cytotoxic chemotherapy, the established radical treatment is primary wide resection. The effects of histone deacetylase (HDAC) inhibitors on myxofibrosarcoma have not yet been investigated. Therefore, the main purpose of the present study was to examine the effects of a HDAC inhibitor on myxofibrosarcoma., Methods: The effects of the HDAC inhibitor OBP-801 on human myxofibrosarcoma cells were examined using cell viability assay, flow cytometric analysis of the cell cycle and apoptosis, and Western blotting. The effects of combinations of OBP-801 with pazopanib or Akt-mTOR inhibitors were also investigated using cell viability assay., Results: OBP-801 inhibited the growth of myxofibrosarcoma NMFH-1 and NMFH-2 cells. It also induced cell cycle arrest at the G2 phase and apoptosis in both cell lines. The inhibitory effects of pazopanib and Akt-mTOR inhibitors on the growth of myxofibrosarcoma cells were enhanced by the combination with OBP-801., Conclusions: The present results demonstrated that OBP-801 exerted therapeutic effects in myxofibrosarcoma in both single and concomitant administrations. Therefore, OBP-801 has potential as a novel treatment for myxofibrosarcoma.