Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma

Abstract

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

ACAT1 promotes proliferation and metastasis of bladder cancer via AKT/GSK3β/c-Myc signaling pathway

“…Flow cytometry, MTT and colony formation assays as well as transwell and wound healing assays also demonstrated that the cell cycle regulation, cell proliferation and migration affected by ACAT1 knockdown or overexpression can be reversed by SC79 or MK2206. RNA-seq heatmap analysis and qRT-PCR validation confirmed the downregulation of c-Myc downstream molecules in ACAT1 knockdown BLCA cells, linking these molecules to cell cycle regulation and proliferation in various malignancies, including glioblastoma [52,53], nasopharyngeal carcinoma [54], esophageal cancer [55], breast cancer [56,57], cervical cancer [58], lung cancer [59], liver cancer [60][61][62], bladder cancer [63], prostate cancer [64], acute myeloid leukemia [65] and diffuse large B-cell lymphoma [66]. In addition, reports on c-Myc-regulated downstream molecules involved in EMT, such as POLD2 [52], TMEM97 [56], DCTPP1 [64], MCM6 [61] and CBX3 [53], have been published.…”

Prognostic and Immune Landscape Analysis of Ubiquitination-related Genes in Hepatocellular Carcinoma: Based on Bulk and Single-cell RNA Sequencing Data

“…Mounting evidence suggests that ubiquitination, along with its reverse process, deubiquitination, plays crucial regulatory roles in innate and adaptive immune responses by modulating the functions of diverse immune cells. For instance, ubiquitination regulates apoptosis and autophagy in macrophages 28 , MHC II expression in dendritic cells 29 , TCR signaling and T cell activation 30 , as well as B cell development and activation 31 . Ubiquitination research has primarily focused on the phenotypic changes induced by individual proteins.…”

Targeting MYC-driven lymphoma: lessons learned and future directions

“…However, the most advanced MYC/MAX dimerization inhibitor in clinical development is Omomyc, a MYC dominant negative based on the basic helix-loop-helix leucine zipper (b-HLH-Z) domain of the human c-MYC protein, able to form homodimers and heterodimers with MYC and MAX and interfere with MYC transcriptional activity. Omomyc has been used in its transgenic form in BL, in murine lymphoma cell lines obtained from Eμ-myc transgenic mice and in Raji cells (wild-type or knock out for FBXO11) in vitro and in vivo (subcutaneous xenografts), alone or in combination with the BCL6 degrader BI-3802 [99] . In this context, Omomyc blocked cell proliferation and increased apoptosis, effects further improved by combined BCL6 targeting.…”