Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma

Abstract

Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.

A Novel Defined Super-Enhancer Associated Gene Signature to Predict Prognosis in Patients With Diffuse Large B-Cell Lymphoma

“…As for the protective prognostic factors in our study, PXK encoding protein is involved in ligand-induced internalization, synaptic transmits, and degradation of epidermal growth factor receptors associated with some autoimmunity diseases ( Takeuchi et al, 2010 ). B-cell translocation gene 1 (BTG1) belongs to an anti-proliferative gene family, which regulates autophagy and the cell cycle and is also implicated in DNA repair and mRNA stability ( Xue et al, 2021 ). BTG1 is a well-characterized tumor suppressor for both solid tumors and hematopoiesis and recently has been reported to have a novel role in genotoxic and integrated stress responses.…”

Epigenetic targets in B- and T-cell lymphomas: latest developments

“…218 There are several studies using the ChIP technique to confirm whether alterations in chromatin structure and expression of certain genes are restored after epidrug treatment. [219][220][221] MS has been used to determine the altered structure of proteins of interest, although there are limitations in recognizing the large number of ions inherent to histones or other cellular proteins. Different algorithms have been developed depending on the integrity of the quantified protein (total, peptides or amino acids), THRASH journals.sagepub.com/home/tah TherapeuTic advances in hematology being one of the most versioned although it still depends on the structural reference database.…”

Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment

“…rituximab/chemotherapy resistant B-cell lymphoma (RRCL) patients are characterized with poor prognosis, while tucidinostat reverses the chemotherapeutic resistance through B-cell translocation gene 1 (BTG1)-mediated autophagy. Tucidinostat shows synergistic effect with chemotherapeutics, such as etoposide, cisplatin, gemcitabine, in RRCL cell lines (Xue et al, 2021). Zhang et al showed that tucidinostat and doxorubicin exhibited a synergistic effect in 2 PTCL cell lines through increased DNA damage and apoptosis (Zhang et al, 2017).…”