Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma
Xi-Ya Li, Jichuan Wu, Ping Liu, Zi-Juan Li, Yong Wang, Bingyi Chen, Cheng-Long Hu, Ming-Yue Fei, Pengcheng Yu, Yi-Lun Jiang, Chunhui Xu, Bin-He Chang, Xin-Chi Chen, Li-Juan Zong, Jiaying Zhang, Ying Fang, Xiao‐Jian Sun, Kai Xue, Li Wang, Shu-Bei Chen, Shiyu Jiang, Ailing Gui, Ling Yang, Juan Gu, Baohua Yu, Qunling Zhang, Lan Wang, Lan Wang, Lan Wang
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.