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Nat Cell Biol. 2018 May;20(5):586-596. doi: 10.1038/s41556-018-0084-5. Epub 2018 Apr 25.

Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2.

Author information

1
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
2
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
4
The Stowers Institute of Medical Research, Kansas City, MO, USA.
5
Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA.
6
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA. businol@upenn.edu.
9
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. businol@upenn.edu.

Abstract

Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6. A non-degradable roquin2(Y691F) mutant requires its RNA-binding ability to phenocopy the effect of KLHL6 loss. Stabilization of roquin2 promotes mRNA decay of the tumour suppressor and NF-κB pathway inhibitor, tumour necrosis factor-α-inducible gene 3. Collectively, our findings uncover the tumour suppressing mechanism of KLHL6.

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