PMID- 31497350
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 9
IP  - 8
DP  - 2019
TI  - Disruption of the menin-MLL interaction triggers menin protein degradation via 
      ubiquitin-proteasome pathway.
PG  - 1682-1694
AB  - 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.
FAU - Wu, Yuan
AU  - Wu Y
AD  - Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan 
      University Wuhan 430071, China.
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
AD  - Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology Wuhan 430071, China.
FAU - Doepner, Miriam
AU  - Doepner M
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Hojnacki, Taylor
AU  - Hojnacki T
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Feng, Zijie
AU  - Feng Z
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Katona, Bryson W
AU  - Katona BW
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
AD  - Division of Gastroenterology, Department of Medicine, Perelman School of 
      Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 19014, PA, 
      USA.
FAU - He, Xin
AU  - He X
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Ma, Jian
AU  - Ma J
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Cao, Yan
AU  - Cao Y
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Busino, Luca
AU  - Busino L
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
FAU - Zhou, Fuxiang
AU  - Zhou F
AD  - Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan 
      University Wuhan 430071, China.
FAU - Hua, Xianxin
AU  - Hua X
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 
      School of Medicine, University of Pennsylvania 421 Curie Blvd., Philadelphia 
      19014, PA, USA.
LA  - eng
GR  - R25 HD082842/HD/NICHD NIH HHS/United States
PT  - Journal Article
DEP - 20190801
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC6726985
OTO - NOTNLM
OT  - Menin
OT  - leukemia
OT  - menin-MLL inhibitor
OT  - ubiquitin-proteasome pathway
COIS- None.
EDAT- 2019/09/10 06:00
MHDA- 2019/09/10 06:01
PMCR- 2019/08/01
CRDT- 2019/09/10 06:00
PHST- 2019/07/03 00:00 [received]
PHST- 2019/07/11 00:00 [accepted]
PHST- 2019/09/10 06:00 [entrez]
PHST- 2019/09/10 06:00 [pubmed]
PHST- 2019/09/10 06:01 [medline]
PHST- 2019/08/01 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2019 Aug 1;9(8):1682-1694. eCollection 2019.