Highlights d SETD2-mediated EZH2-K735me1 licenses EZH2 destruction to impede PCa metastasis d Cancer-associated SETD2 mutation (R1523H) disrupts SETD2-EZH2 interaction d Metformin treatment might combat EZH2-high PCa by stimulating SETD2 expression

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The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.

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Highlights d The H3K36me2 methyltransferase Nsd2 is highly expressed in GCB cells d Nsd2 is required for GCB cell adhesion to FDC-expressed adhesion molecules d Loss of Nsd2 leads to reduced BCR signal and antigen acquisition of GCB cells d Nsd2 deficiency impairs GCB cell affinity maturation