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Am J Cancer Res. 2019 Aug 1;9(8):1682-1694. eCollection 2019.

Disruption of the menin-MLL interaction triggers menin protein degradation via ubiquitin-proteasome pathway.

Author information

1
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University Wuhan 430071, China.
2
Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 19014, PA, USA.
3
Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430071, China.
4
Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 19014, PA, USA.

Abstract

Menin, a protein encoded by the MEN1 gene, suppresses cancers associated with multiple endocrine neoplasia type 1 (MEN1), but promotes the development of a subset of leukemia induced by mixed lineage leukemia (MLL)-derived fusion proteins (MLL-FPs). The crystal structure of menin indicates that it acts as a scaffold protein to bind the N-terminus of MLL via a central pocket. Small molecule menin-MLL inhibitors (MIs) bind the menin pocket to disrupt the menin/MLL interaction, resulting in suppression of MLL-FP-transformed acute myeoloid leukemia (AML). It is thought that MIs suppress the MLL-FP-induced leukemia by blocking the menin/MLL interaction and menin/MLL-induced HOX gene transcription. However, it is not clear whether MIs also affect other aspects of menin biology beyond disruption of the menin/MLL interaction. Here we show for the first time that MIs reduced menin protein levels and decreased the half-life of menin protein but have no effect on mRNA level in MLL-FP-expressing leukemia cells, and proteasome or E1 ligase inhibitor rescued the MI-induced menin degradation. Notably, the MI-induced reduction of H3K4m3 and HOXA9 expression was rescued with a proteasome inhibitor that blocks MI-induced menin protein degradation. Mechanistically, MIs promote the interaction of menin with Hsp70-associated ubiquitin ligase CHIP, resulting in increased menin ubiquitination, leading to increased menin degradation. Together, these findings uncover a novel mechanism whereby small molecule MIs increase menin degradation by triggering the Hsp70/CHIP-mediated ubiquitin-proteasome pathway that ultimately leads to the reduction in HOXA9 gene expression and leukemia suppression.

KEYWORDS:

Menin; leukemia; menin-MLL inhibitor; ubiquitin-proteasome pathway

PMID:
31497350
PMCID:
PMC6726985

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