PMID- 29550418
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20211204
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 138
IP  - 8
DP  - 2018 Aug
TI  - SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal 
      Cell Carcinomas.
PG  - 1716-1725
LID - S0022-202X(18)30229-X [pii]
LID - 10.1016/j.jid.2018.01.040 [doi]
AB  - Currently available smoothened targeted therapies in patients with basal cell 
      nevus syndrome are associated with substantial tumor recurrence and clinical 
      resistance. Strategies bypassing smoothened and/or identifying additional 
      downstream components of the Hedgehog pathway could provide novel antitumor 
      targets with a better therapeutic index. Sry-related high mobility group box 9 
      (SOX9) is a Hedgehog/glioma-associated oncogene homolog-regulated transcription 
      factor known to be overexpressed in basal cell carcinomas (BCCs). A sequence 
      motif search for SOX9-responsive elements identified three motifs in the promoter 
      region of mammalian target of rapamycin (mTOR). In murine BCC cells, SOX9 
      occupies the mTOR promoter and induces its transcriptional activity. Short 
      hairpin RNA (shRNA)-mediated knockdown of SOX9, as well as smoothened inhibition 
      by itraconazole and vismodegib, reduces mTOR expression and the phosphorylation 
      of known downstream mTOR targets. These effects culminate in diminishing the 
      proliferative capacity of BCC cells, demonstrating a direct mechanistic link 
      between the Hedgehog and mTOR pathways capable of driving BCC growth. 
      Furthermore, rapamycin, a pharmacologic mTOR inhibitor, suppressed the growth of 
      UV-induced BCCs in Ptch1(+/-)/SKH-1 mice, a model that closely mimics the 
      accelerated BCC growth pattern of patients with basal cell nevus syndrome. Our 
      data demonstrate that Hedgehog signaling converges on mTOR via SOX9, and 
      highlight the SOX9-mTOR axis as a viable additional target downstream of 
      smoothened that could enhance tumor elimination in patients with BCC.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Kim, Arianna L
AU  - Kim AL
AD  - Department of Dermatology, Columbia University Medical Center, New York, New 
      York, USA. Electronic address: ak309@cumc.columbia.edu.
FAU - Back, Jung Ho
AU  - Back JH
AD  - Department of Dermatology, Columbia University Medical Center, New York, New 
      York, USA.
FAU - Chaudhary, Sandeep C
AU  - Chaudhary SC
AD  - Department of Dermatology, University of Alabama at Birmingham, Birmingham, 
      Alabama, USA.
FAU - Zhu, Yucui
AU  - Zhu Y
AD  - Department of Dermatology, Columbia University Medical Center, New York, New 
      York, USA.
FAU - Athar, Mohammad
AU  - Athar M
AD  - Department of Dermatology, University of Alabama at Birmingham, Birmingham, 
      Alabama, USA.
FAU - Bickers, David R
AU  - Bickers DR
AD  - Department of Dermatology, Columbia University Medical Center, New York, New 
      York, USA.
LA  - eng
GR  - P30 AR069632/AR/NIAMS NIH HHS/United States
GR  - R01 ES020344/ES/NIEHS NIH HHS/United States
GR  - R01 ES026219/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180314
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (SOX9 protein, human)
RN  - 0 (Smoothened Receptor)
RN  - 0 (Sox9 protein, mouse)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/therapeutic use
MH  - Carcinoma, Basal Cell/drug therapy/*genetics/pathology
MH  - Carcinoma, Squamous Cell/drug therapy/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - HEK293 Cells
MH  - Hedgehog Proteins/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Hairless
MH  - Neoplasm Recurrence, Local
MH  - Neoplasms, Experimental/drug therapy/etiology/pathology
MH  - Phosphorylation/drug effects
MH  - Promoter Regions, Genetic/genetics
MH  - RNA, Small Interfering/metabolism
MH  - SOX9 Transcription Factor/genetics/*metabolism
MH  - Signal Transduction/genetics
MH  - Skin/pathology
MH  - Skin Neoplasms/drug therapy/*genetics/pathology
MH  - Smoothened Receptor/antagonists & inhibitors/metabolism
MH  - TOR Serine-Threonine Kinases/*genetics/metabolism
MH  - Tissue Array Analysis
MH  - Ultraviolet Rays/adverse effects
PMC - PMC6056318
MID - NIHMS967760
COIS- CONFLICT OF INTEREST The authors state no conflict of interest.
EDAT- 2018/03/20 06:00
MHDA- 2019/06/14 06:00
PMCR- 2018/08/01
CRDT- 2018/03/19 06:00
PHST- 2017/11/16 00:00 [received]
PHST- 2018/01/17 00:00 [revised]
PHST- 2018/01/28 00:00 [accepted]
PHST- 2018/03/20 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2018/03/19 06:00 [entrez]
PHST- 2018/08/01 00:00 [pmc-release]
AID - S0022-202X(18)30229-X [pii]
AID - 10.1016/j.jid.2018.01.040 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2018 Aug;138(8):1716-1725. doi: 10.1016/j.jid.2018.01.040. 
      Epub 2018 Mar 14.