PMID- 38141761
OWN - NLM
STAT- MEDLINE
DCOM- 20240213
LR  - 20240213
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 300
IP  - 1
DP  - 2024 Jan
TI  - PP2A inhibitor SET promotes mTORC1 and Bmi1 signaling through Akt activation and 
      maintains the colony-formation ability of cancer cells.
PG  - 105584
LID - S0021-9258(23)02612-1 [pii]
LID - 10.1016/j.jbc.2023.105584 [doi]
LID - 105584
AB  - Protein phosphatase 2A (PP2A) is an essential tumor suppressor, with its activity 
      often hindered in cancer cells by endogenous PP2A inhibitory proteins like SE 
      translocation (SET). SET/PP2A axis plays a pivotal role in the colony-formation 
      ability of cancer cells and the stabilization of c-Myc and E2F1 proteins 
      implicated in this process. However, in osteosarcoma cell line HOS, SET 
      knock-down (KD) suppresses the colony-formation ability without affecting c-Myc 
      and E2F1. This study aimed to unravel the molecular mechanism through which SET 
      enhances the colony-formation ability of HOS cells and determine if it is 
      generalized to other cancer cells. Transcriptome analysis unveiled that SET KD 
      suppressed mTORC1 signaling. SET KD inhibited Akt phosphorylation, an upstream 
      kinase for mTORC1. PP2A inhibitor blocked SET KD-mediated decrease in 
      phosphorylation of Akt and a mTORC1 substrate p70S6K. A constitutively active Akt 
      restored decreased colony-formation ability by SET KD, indicating the 
      SET/PP2A/Akt/mTORC1 axis. Additionally, enrichment analysis highlighted that 
      Bmi-1, a polycomb group protein, is affected by SET KD. SET KD decreased Bmi-1 
      protein by Akt inhibition but not by mTORC1 inhibition, and exogenous Bmi-1 
      expression rescued the reduced colony formation by SET KD. Four out of eight 
      cancer cell lines exhibited decreased Bmi-1 by SET KD. Further analysis of these 
      cell lines revealed that Myc activity plays a role in SET KD-mediated Bmi-1 
      degradation. These findings provide new insights into the molecular mechanism of 
      SET-regulated colony-formation ability, which involved Akt-mediated activation of 
      mTORC1/p70S6K and Bmi-1 signaling.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Kohyanagi, Naoki
AU  - Kohyanagi N
AD  - Laboratory of Veterinary Pharmacology, Yamaguchi University Joint Graduate School 
      of Veterinary Medicine, Yamaguchi, Japan.
FAU - Kitamura, Nao
AU  - Kitamura N
AD  - Laboratory of Veterinary Pharmacology, Yamaguchi University Joint Graduate School 
      of Veterinary Medicine, Yamaguchi, Japan.
FAU - Ikeda, Shunta
AU  - Ikeda S
AD  - Laboratory of Veterinary Pharmacology, Yamaguchi University Joint Graduate School 
      of Veterinary Medicine, Yamaguchi, Japan.
FAU - Shibutani, Shusaku
AU  - Shibutani S
AD  - Laboratory of Veterinary Hygiene, Yamaguchi University Joint Graduate School of 
      Veterinary Medicine, Yamaguchi, Japan.
FAU - Sato, Koichi
AU  - Sato K
AD  - Laboratory of Veterinary Pharmacology, Yamaguchi University Joint Graduate School 
      of Veterinary Medicine, Yamaguchi, Japan.
FAU - Ohama, Takashi
AU  - Ohama T
AD  - Laboratory of Veterinary Pharmacology, Yamaguchi University Joint Graduate School 
      of Veterinary Medicine, Yamaguchi, Japan. Electronic address: 
      t.ohama@yamaguchi-u.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20231222
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (BMI1 protein, human)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.3.2.27 (Polycomb Repressive Complex 1)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (SET protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Histone Chaperones)
RN  - 0 (MYC protein, human)
SB  - IM
MH  - Humans
MH  - *Enzyme Inhibitors/metabolism
MH  - *Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - *Neoplasms/metabolism/pathology
MH  - Phosphorylation
MH  - *Polycomb Repressive Complex 1/metabolism
MH  - *Protein Phosphatase 2/antagonists & inhibitors/metabolism
MH  - *Proto-Oncogene Proteins c-akt/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *DNA-Binding Proteins/deficiency/genetics/metabolism
MH  - *Histone Chaperones/deficiency/genetics/metabolism
MH  - Signal Transduction
MH  - Enzyme Activation
MH  - Cell Line, Tumor
PMC - PMC10826185
OTO - NOTNLM
OT  - Akt/PKB
OT  - Bmi-1
OT  - SET
OT  - cancer biology
OT  - mammalian target of rapamycin
OT  - polycomb
OT  - protein phosphatase 2A
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2023/12/24 09:41
MHDA- 2024/02/05 06:43
PMCR- 2023/12/22
CRDT- 2023/12/23 19:25
PHST- 2023/06/23 00:00 [received]
PHST- 2023/11/19 00:00 [revised]
PHST- 2023/12/07 00:00 [accepted]
PHST- 2024/02/05 06:43 [medline]
PHST- 2023/12/24 09:41 [pubmed]
PHST- 2023/12/23 19:25 [entrez]
PHST- 2023/12/22 00:00 [pmc-release]
AID - S0021-9258(23)02612-1 [pii]
AID - 105584 [pii]
AID - 10.1016/j.jbc.2023.105584 [doi]
PST - ppublish
SO  - J Biol Chem. 2024 Jan;300(1):105584. doi: 10.1016/j.jbc.2023.105584. Epub 2023 
      Dec 22.