Targeting HDACs for diffuse large B-cell lymphoma therapy

Abstract

Histone deacetylases (HDACs) are involved in tumorigenesis and progression, however, their role in diffuse large B-cell lymphoma (DLBCL) is not well understood. In this study, we examined the expression levels, mutations, and clinical significance of HDACs in DLBCL. Additionally, we investigated the therapeutic potential of Chidamide, a novel HDAC inhibitor, to provide scientific evidence for targeting HDACs in DLBCL patients. We extracted transcriptome data of DLBCLs––including 47 lymph node samples and 337 whole-blood-cell controls––from The Cancer Genome Atlas. Bioinformatic analyses of HDAC expression, mutation, and correlation with the clinical significance of DLBCL patients were performed with the Gene Expression Profiling Interactive Analysis, GENEMANIA, and web-based software including cBioPortal and WebGestalt. To examine the therapeutic effect of Chidamide, DLBCL cell lines (WSU-DLCL-2 and DB cells) were employed. Cell proliferation and apoptosis were analyzed with Cell Counting Kit-8 and flow cytometry assays. The impact of Chidamide treatment was also analyzed by RNA sequencing of treated DB cells. Western blot was used to explore the molecular mechanism of the cytotoxicity of Chidamide on DLBCL cell lines. The expression of some HDACs (HDAC1, 2, 3, 4, 6, 7, 8, and 9) were significantly higher in the lymph node samples of DLBCL than that in whole-blood-cell controls. Moreover, we found that the mutation rate of HDACs was also higher in DLBCL tissues, although the overall survival of DLBCL patients was not associated with HDAC expression. Chidamide was found to have a cytotoxic effect on DLBCL cells in a dose-dependent manner, while transcriptome analysis and western blot revealed that using it for treatment impacted several biological processes, including PI3K/AKT signaling, mTOR signaling, the cell cycle, and apoptosis pathways. Alterations of HDAC genes, including enhanced expression and mutations, are positively related to DLBCL. Targeting HDACs with specific inhibitors such as Chidamide may represent a potential therapeutic approach for DLBCL patients.

Discovery of a Highly Potent and Selective HDAC8 Degrader: Advancing the Functional Understanding and Therapeutic Potential of HDAC8

“…Diffuse large B cell lymphoma (DLBCL) is a particularly aggressive subtype of non-Hodgkin lymphoma. 38 DLBCL has been reported to respond to HDAC inhibitors, 39,40 and gene expression analysis in clinical samples also showed a significant HDAC8 upregulation in patient samples (Figure S3), indicating a critical role for HDAC8 in promoting DLBCL.…”

“…White solid, 10.5 mg, 42% yield for two steps. 1 (40). White solid, 13.3 mg, 49% yield for two steps.…”

“…Diffuse large B cell lymphoma (DLBCL) is a particularly aggressive subtype of non-Hodgkin lymphoma . DLBCL has been reported to respond to HDAC inhibitors, , and gene expression analysis in clinical samples also showed a significant HDAC8 upregulation in patient samples (Figure S3), indicating a critical role for HDAC8 in promoting DLBCL. In this study, we revealed, for the first time, that HDAC8 degradation by YX862 can induce robust on-target antiproliferative activity in DLBCL SU-DHL-2 and DoHH2 cells.…”

shRNA-mediated gene silencing of HDAC11 empowers CAR-T cells against prostate cancer

“…Downregulation of the HDAC11 gene can boost the effector as well as memory function of T cells as described in previously published data ( 12 ). Knockdown of HDAC11 in mice increased T cell lymphoma aggressiveness as compared to wild-type ( 13 , 14 ). Due to the nonredundant nature of epigenetic enzymes, modulating the gene expression of even a single epigenetic enzyme can change the overall expression profile of CAR-T cells ( 11 ).…”

The efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of hemophagocytic lymphohistiocytosis in adult patients: an open-label, single-center study

“…Chidamide is a novel selective histone deacetylase inhibitor (HDACi) that has been shown to promote the recovery of normal immune function ( 6 , 7 )and treat potential causes ( 8 , 9 )of HLH, thereby ending the inflammatory cytokine storm. HDACi can also sensitize etoposide (VP-16) by promoting the activation of caspase 8 and caspase 3, upregulating the expression of topoisomerase II, and promoting the degradation of DNA repair kinases ( 10 ).…”