PMID- 37477952
OWN - NLM
STAT- MEDLINE
DCOM- 20230803
LR  - 20240102
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 480
IP  - 15
DP  - 2023 Aug 16
TI  - SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer.
PG  - 1199-1216
LID - 10.1042/BCJ20220439 [doi]
AB  - Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI 
      family of transcription factors (TF) is stimulated, is commonly observed in 
      cancer cells. One well-established mechanism of this increased activity is 
      through the inactivation of Suppressor of Fused (SUFU), a negative regulator of 
      the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity 
      and induction of target gene expression. Here, we demonstrate a novel role for 
      SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In 
      non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression 
      increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU 
      reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI 
      target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates 
      down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC 
      cell viability, and overexpression of BCL2 partially rescues the effect of 
      reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a 
      major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU 
      and GLI1 in the nucleus through previously characterized domains. Chromatin 
      immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the 
      promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 
      activity without affecting its protein stability. Through our findings, we 
      propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a 
      new mechanism of Hh/GLI signaling pathway regulation in cancer cells.
CI  - (c) 2023 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Paradise, Brooke D
AU  - Paradise BD
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 
      55905, U.S.A.
FAU - Gainullin, Vladimir G
AU  - Gainullin VG
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Almada, Luciana L
AU  - Almada LL
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Sigafoos, Ashley N
AU  - Sigafoos AN
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Sen, Sandhya
AU  - Sen S
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Vera, Renzo E
AU  - Vera RE
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Raja Arul, Glancis Luzeena
AU  - Raja Arul GL
AUID- ORCID: 0000-0002-7672-8597
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 
      55905, U.S.A.
FAU - Toruner, Murat
AU  - Toruner M
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
FAU - Pease, David R
AU  - Pease DR
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 
      55905, U.S.A.
FAU - Gonzalez, Alina L
AU  - Gonzalez AL
AD  - Facultad de Ciencias Exactas y Naturales, Instituto de Ciencias de la Tierra y 
      Ambientales de La Pampa (INCITAP), Universidad Nacional de La Pampa - Consejo 
      Nacional de Investigaciones Cientificas y Tecnicas (UNLPam-CONICET), La Pampa 
      6300, Argentina.
FAU - Mentucci, Fatima M
AU  - Mentucci FM
AD  - Department of Pharmacy, University of Salerno, Salerno 84084, Italy.
FAU - Grasso, Daniel H
AU  - Grasso DH
AD  - Instituto de Estudios de la Inmunidad Humoral (IDEHU), Escuela de Farmacia y 
      Bioquimica, Universidad de Buenos Aires, Ciudad Autonoma de Buenos Aires 1113, 
      Argentina.
FAU - Fernandez-Zapico, Martin E
AU  - Fernandez-Zapico ME
AUID- ORCID: 0000-0002-8089-3907
AD  - Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, U.S.A.
LA  - eng
GR  - P50 CA102701/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Repressor Proteins)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (SUFU protein, human)
SB  - IM
MH  - Humans
MH  - *Repressor Proteins/genetics/metabolism
MH  - Zinc Finger Protein GLI1/genetics
MH  - Hedgehog Proteins/genetics/metabolism
MH  - Transcription Factors/genetics/metabolism
MH  - *Pancreatic Neoplasms/genetics
MH  - Proto-Oncogene Proteins c-bcl-2
OTO - NOTNLM
OT  - BCL2
OT  - GLI1
OT  - SUFU
OT  - cell survival
OT  - pancreatic cancer
EDAT- 2023/07/21 13:15
MHDA- 2023/08/03 06:42
CRDT- 2023/07/21 11:52
PHST- 2022/08/21 00:00 [received]
PHST- 2023/07/20 00:00 [revised]
PHST- 2023/07/21 00:00 [accepted]
PHST- 2023/08/03 06:42 [medline]
PHST- 2023/07/21 13:15 [pubmed]
PHST- 2023/07/21 11:52 [entrez]
AID - 233309 [pii]
AID - 10.1042/BCJ20220439 [doi]
PST - ppublish
SO  - Biochem J. 2023 Aug 16;480(15):1199-1216. doi: 10.1042/BCJ20220439.