The ubiquitin-proteasome system (UPS) plays a critical role in the maintenance of cellular homeostasis as it mediates the precise and temporal degradation of intracellular proteins and affects a variety of cellular processes. The misregulation of the ubiquitin-proteasome system (UPS) can result in the pathogenesis of human diseases including cancer. A proteasome inhibitor has been proven an effective treatment for lymphoid malignancies, rendering the UPS appealing as a new therapeutic target for cancer. Despite the significant progress, much more remains to be explored in the field of ubiquitin and molecular mechanisms of tumorigenesis. KLHL6 is a frequently mutated in mature B-cell cancers, but the relevance of these mutations and molecular function of KLHL6 are currently not known. Here, we show that KLHL6 is a novel E3 ubiquitin ligase and cancer-associated somatic mutations disrupt its catalytic activity. Via proteomic analysis and mutagenesis screening approaches, we have further identified and validated Roquin2, a mRNA decay factor, as a substrate of KLHL6. The interaction between KLHL6 and Roquin2 requires a tyrosine in position 691 of Roquin2 and can be inhibited when tyrosine 691 is phosphorylated. Furthermore, using in vitro cell proliferation assays and xenograft mouse models, we show that KLHL6 has tumor suppressive effects that are dependent on Roquin2 stabilization in diffuse large B-cell lymphoma (DLBCL). RNA sequencing analysis has revealed that Roquin2 regulated genes are implicated in the NF-κB pathway and as lymphoid tumor suppressors, correlating with B-cell lymphoma proliferation and survival. Taken together, the work described here highlights a previously uncharacterized molecular mechanism whereby the novel E3 ligase modulates mRNA decay through its substrate degradation and plays role in the pathogenesis of mature B-cell cancers.