SQSTM1/p62 predicts prognosis and upregulates the transcription of CCND1 to promote proliferation in mantle cell lymphoma.

Abstract

Mantle cell lymphoma (MCL) is a rare, highly invasive non-Hodgkin's lymphoma. The main pathogenesis of MCL is associated with the formation of the IgH/CCND1 fusion gene and nuclear overexpression of cyclin D1, which accelerates the cell cycle, leading to tumorigenesis. The prognosis with current standard chemotherapy is still unsatisfactory. SQSTM1/p62 is a multifunctional adaptor that plays an important role in various tumors. Here, we found that the expression of p62 in MCL tissues was higher than that in hyperplastic lymphadenitis patients. Patients with low p62 expression in MCL cells had better overall survival and progression-free survival rates than those with high expression (p = 0.024 and p = 0.025, respectively). Multivariate Cox analysis indicated that the calculated death risk (hazard ratio [HR]) in patients with high expression levels of p62 increased to 2.742 (95% confidence interval (CI) of 1.268-5.852, p = 0.01), which was higher than those with low levels. Silencing p62 impaired Jeko-1 and Granta519 cell proliferation while downregulating CCND1 mRNA and protein expression, thereby inducing G0/G1 cell cycle arrest. However, silencing p62 does not affect the fusion of IgH and CCND1. Luciferase reporter gene analysis and chromatin immunoprecipitation analysis demonstrated that p62 may regulate CCND1 gene expression through Nrf2. These results provide evidence that p62 can predict poor prognosis in MCL. The precise targeting of p62 therapy reduces the promoting effect of Nrf2 on CCND1, thereby preventing cell cycle progression and effectively inhibiting tumor proliferation. Therefore, p62 may provide a potential target for MCL.