PMID- 35794249
OWN - NLM
STAT- MEDLINE
DCOM- 20220809
LR  - 20221104
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 41
IP  - 32
DP  - 2022 Aug
TI  - FOXM1 regulates glycolysis and energy production in multiple myeloma.
PG  - 3899-3911
LID - 10.1038/s41388-022-02398-4 [doi]
AB  - The transcription factor, forkhead box M1 (FOXM1), has been implicated in the 
      natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and 
      relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes 
      the growth of neoplastic plasma cells is poorly understood. Here we show that 
      FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the 
      bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using 
      FOXM1-deficient myeloma cells as principal experimental model system, we find 
      that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in 
      myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 
      inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts 
      using a mechanism that includes enhanced proteasomal FOXM1 degradation. 
      Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 
      (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing 
      down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism 
      and underscore the feasibility of targeting FOXM1 for new approaches to myeloma 
      therapy and prevention.
CI  - (c) 2022. The Author(s).
FAU - Cheng, Yan
AU  - Cheng Y
AUID- ORCID: 0000-0001-7877-9622
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Sun, Fumou
AU  - Sun F
AUID- ORCID: 0000-0003-2034-3492
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Thornton, Krista
AU  - Thornton K
AD  - Department of Pathology Master of Science Graduate Program, University of Iowa, 
      Iowa City, IA, USA.
FAU - Jing, Xuefang
AU  - Jing X
AUID- ORCID: 0000-0002-8670-4505
AD  - Department of Pathology, University of Iowa, Iowa City, IA, USA.
FAU - Dong, Jing
AU  - Dong J
AUID- ORCID: 0000-0001-9856-5963
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Yun, Grant
AU  - Yun G
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Pisano, Michael
AU  - Pisano M
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
AD  - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, 
      IA, USA.
FAU - Zhan, Fenghuang
AU  - Zhan F
AUID- ORCID: 0000-0001-5417-2973
AD  - Myeloma Center, Division of Hematology and Oncology, Department of Medicine, and 
      Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical 
      Sciences, Little Rock, AR, USA.
FAU - Kim, Sung Hoon
AU  - Kim SH
AD  - Departments of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 
      USA.
FAU - Katzenellenbogen, John A
AU  - Katzenellenbogen JA
AUID- ORCID: 0000-0003-0914-0010
AD  - Departments of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 
      USA.
FAU - Katzenellenbogen, Benita S
AU  - Katzenellenbogen BS
AUID- ORCID: 0000-0002-8847-2752
AD  - Molecular and Integrative Physiology, and Cancer Center at Illinois, University 
      of Illinois at Urbana-Champaign, Urbana, IL, USA.
FAU - Hari, Parameswaran
AU  - Hari P
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
AD  - Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
FAU - Janz, Siegfried
AU  - Janz S
AUID- ORCID: 0000-0002-2229-5511
AD  - Division of Hematology and Oncology, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI, USA. sjanz@mcw.edu.
AD  - Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA. sjanz@mcw.edu.
LA  - eng
GR  - R42 CA180190/CA/NCI NIH HHS/United States
GR  - R01 CA151354/CA/NCI NIH HHS/United States
GR  - P30 CA086862/CA/NCI NIH HHS/United States
GR  - R41 CA180190/CA/NCI NIH HHS/United States
GR  - R01 CA236814/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220706
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (FOXM1 protein, human)
RN  - 0 (Forkhead Box Protein M1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Forkhead Box Protein M1/genetics/metabolism
MH  - Forkhead Transcription Factors/genetics/metabolism
MH  - Gene Expression Regulation
MH  - Gene Expression Regulation, Neoplastic
MH  - Glycolysis
MH  - Humans
MH  - Mice
MH  - *Multiple Myeloma/genetics/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC9355869
COIS- The authors declare no competing interests.
EDAT- 2022/07/07 06:00
MHDA- 2022/08/10 06:00
PMCR- 2022/07/06
CRDT- 2022/07/06 23:28
PHST- 2022/01/06 00:00 [received]
PHST- 2022/06/21 00:00 [accepted]
PHST- 2022/06/16 00:00 [revised]
PHST- 2022/07/07 06:00 [pubmed]
PHST- 2022/08/10 06:00 [medline]
PHST- 2022/07/06 23:28 [entrez]
PHST- 2022/07/06 00:00 [pmc-release]
AID - 10.1038/s41388-022-02398-4 [pii]
AID - 2398 [pii]
AID - 10.1038/s41388-022-02398-4 [doi]
PST - ppublish
SO  - Oncogene. 2022 Aug;41(32):3899-3911. doi: 10.1038/s41388-022-02398-4. Epub 2022 
      Jul 6.