PMID- 34203850
OWN - NLM
STAT- MEDLINE
DCOM- 20210713
LR  - 20240402
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 12
DP  - 2021 Jun 15
TI  - Hydrophobic Tagging-Mediated Degradation of Transcription Coactivator SRC-1.
LID - 10.3390/ijms22126407 [doi]
LID - 6407
AB  - Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a 
      pivotal role in mediating a wide range of signaling pathways by interacting with 
      related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 
      activity is associated with cancer metastasis and progression, and therefore, 
      suppression of SRC-1 is emerging as a promising therapeutic strategy. In this 
      study, we developed a novel SRC-1 degrader for targeted degradation of cellular 
      SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky 
      hydrophobic group. Since the hydrophobic moiety on the protein surface could 
      mimic a partially denatured hydrophobic region of a protein, SRC-1 could be 
      recognized as an unfolded protein and experience the chaperone-mediated 
      degradation in the cells through the ubiquitin-proteasome system (UPS). Our 
      results demonstrate that a hydrophobic-tagged chimeric molecule is shown to 
      significantly reduce cellular levels of SRC-1 and suppress cancer cell migration 
      and invasion. Together, these results highlight that our SRC-1 degrader 
      represents a novel class of therapeutic candidates for targeting cancer 
      metastasis. Moreover, we believe that the hydrophobic tagging strategy would be 
      widely applicable to develop peptide-based protein degraders with enhanced 
      cellular activity.
FAU - Choi, So Ra
AU  - Choi SR
AD  - Department of Chemistry and Division of Advanced Material Science, Pohang 
      University of Science and Technology (POSTECH), Pohang 37673, Korea.
FAU - Wang, Hee Myeong
AU  - Wang HM
AD  - Department of Chemistry and Division of Advanced Material Science, Pohang 
      University of Science and Technology (POSTECH), Pohang 37673, Korea.
FAU - Shin, Min Hyeon
AU  - Shin MH
AUID- ORCID: 0000-0001-6205-2621
AD  - Department of Chemistry and Division of Advanced Material Science, Pohang 
      University of Science and Technology (POSTECH), Pohang 37673, Korea.
AD  - POSTECH Biotech Center, Pohang 37673, Korea.
FAU - Lim, Hyun-Suk
AU  - Lim HS
AUID- ORCID: 0000-0003-4083-2998
AD  - Department of Chemistry and Division of Advanced Material Science, Pohang 
      University of Science and Technology (POSTECH), Pohang 37673, Korea.
LA  - eng
GR  - NRF-2018R1A4A1024713/National Research Foundation of Korea/
GR  - NRF-2019M3e5d4065251/National Research Foundation of Korea/
GR  - NRF-2019H1A2A1074381/National Research Foundation of Korea/
GR  - NRF-2020M3H1A1075314/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20210615
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antigens, CD)
RN  - 0 (CDH1 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Peptides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 81627-83-0 (Macrophage Colony-Stimulating Factor)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Antigens, CD/genetics/metabolism
MH  - Cadherins/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Membrane Permeability
MH  - Cell Movement
MH  - Humans
MH  - *Hydrophobic and Hydrophilic Interactions
MH  - Macrophage Colony-Stimulating Factor/genetics/metabolism
MH  - Molecular Chaperones/metabolism
MH  - Neoplasm Invasiveness
MH  - Nuclear Receptor Coactivator 1/*metabolism
MH  - Peptides/chemistry
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Protein Stability
MH  - *Proteolysis
MH  - RNA, Messenger/genetics/metabolism
MH  - Trans-Activators/*metabolism
PMC - PMC8232704
OTO - NOTNLM
OT  - PROTACs
OT  - SRC-1 transcriptional coactivator
OT  - cancer metastasis
OT  - hydrophobic tagging
OT  - proteasomal degradation
OT  - ubiquitination
OT  - ubiquitin-proteasome system
COIS- The authors declare no conflict of interest.
EDAT- 2021/07/03 06:00
MHDA- 2021/07/14 06:00
PMCR- 2021/06/15
CRDT- 2021/07/02 01:18
PHST- 2021/05/22 00:00 [received]
PHST- 2021/06/11 00:00 [revised]
PHST- 2021/06/12 00:00 [accepted]
PHST- 2021/07/02 01:18 [entrez]
PHST- 2021/07/03 06:00 [pubmed]
PHST- 2021/07/14 06:00 [medline]
PHST- 2021/06/15 00:00 [pmc-release]
AID - ijms22126407 [pii]
AID - ijms-22-06407 [pii]
AID - 10.3390/ijms22126407 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Jun 15;22(12):6407. doi: 10.3390/ijms22126407.