USP13 mediates resistance to Ibrutinib in diffuse large B-cell lymphoma via augmenting FHL1 stabilization

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid malignancy in the world which is mainly divided to ABC type and GCB type. Ibrutinib benefits patients with ABC subtype DLBCL by inhibiting Bruton's tyrosine kinase (BTK), but there are still a lot of patients who are resistant to Ibrutinib. In this study, we found that post-translational modification played a regulatory role in mediating Ibrutinib resistance in DLBCL. The expression of USP13 was significantly higher in Ibrutinib-resistant U2932 cells compared with Ibrutinib-sensitive WSU-DLCL2 cells, and its expression was further increased both in WSU-DLCL2 and U2932 after exposure to Ibrutinib. USP13 overexpression significantly promoted cell growth and decreased Ibrutinib sensitivity in DLBCL while knockdown of USP13 significantly increased Ibrutinib-induced apoptosis and improved the sensitivity to Ibrutinib. Further studies showed that USP13 interacted with FHL1 and stabilized the expression of FHL1 via deubiquitination, thereby mediating the phosphorylation of ERK1/2, resulting in the decrease expression of Bax and the increase expression of Bcl-xL, thus mediating Ibrutinib resistance in DLBCL. The results of immunohistochemical staining of tumor tissue also indicated that the expression level of USP13 was negatively related to the prognosis of DLBCL patients. These new findings provided an experimental basis for overcoming Ibrutinib resistance in DLBCL and showed that USP13 is a potential therapeutic target and prognostic marker in DLBCL.