Tumor suppressive role of CRL3-KLHL6 in Diffuse Large B-cell Lymphoma

Authors

• J Choi
• K Lee
• K Ingvarsdottir
• R Bonasio
• A Saraf
• L Florens
• MP Washburn
• S Tadros
• MR Green
• L Busino

Abstract

The misregulation of 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. Here we present the function of a novel ubiquitin ligase, KLHL6. KLHL6 is a frequently mutated in mature B-cell cancers, including Diffuse Large B-cell Lymphoma (DLBCL), but the relevance of these mutations is not known. We show that KLHL6 assembles a functional Cullin-Ring Ubiquitin Ligase (CRL). Cancer-associated somatic mutations of KLHL6 inhibit its ubiquitin ligase activity by disrupting the interaction with CULLIN3. In malignant DLBCLs, loss of KLHL6 favors cancer cell growth and survival. Via proteomic analysis, we have further established the mRNA decay factor Roquin2 as the first bona fide substrate of KLHL6. Expression of a non-degradable Roquin2 mutant promotes DLBCL growth through its RNA binding ability, phenocopying the effect of KLHL6 loss. RNA sequencing analysis has revealed that Roquin2 regulated genes are implicated in NF-kB pathway and as lymphoid tumor suppressors. Altogether, our study shows a previously uncharacterized molecular mechanism whereby the KLHL6-Roquin2 axis affects B-cell lymphoma proliferation through modulation of NF-kB activity via mRNA decay.

Scientific Focus Area: Cancer Biology

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