Life science
Medical & healthcare, Drug development

Targeting ELF3-dependent transcription for cancer
therapeutics
Department of Cancer Genome Informatics, Graduate School of Medicine
Assistant Professor Masami Suzuki

Researchmap https://researchmap.jp/msuzukicgi?lang=en

Professor Shinichi Yachida

Researchmap https://researchmap.jp/read0210591?lang=en

The transcription factor E74-like factor 3 (ELF3) is inactivatedin a range of cancers, including biliary tract cancer. Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells byidentifying several previously unknown direct target genes of ELF3
that appear to be implicated in biliary duct carcinogenesis. ELF3
directly repressed ZEB2, a key regulator of epithelial-mesenchymaltransition, and upregulated the expression of cingulin, an integral
element in lumen formation. Loss of ELF3 led to decreased cellcell junctions and enhanced cell motility. ALOX5 and CXCL16
were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipoxygenase and CXCL16 play a role in theimmune response. Conditioned medium from cells overexpressing
ELF3 significantly enhanced the migration of natural killer cells andCD8+ T cells toward the conditioned medium. In a biliary tract cancer xenograft model, activation of ELF3 increased expression of
ELF3-related genes, enhanced the tubular structure of the tumors,and led to a loss of vimentin. Overall, our results indicate that ELF3
is a key regulator of both epithelial integrity and immune responses
in biliary tract cancer.

cogenic transcription. While further studies will be needed to clarify
the tumor suppressive or oncogenic roles of ELF3 in different organsystems, ELF3-dependent transcription might be a driver for cancer progression.
主要図表

Epithelial integrity

EMT-related protein
Defense response

ELF3 regulates cell motility and tumor immunity
Figure 1:図１:
ELF3 regulates cell motility and tumor immunity
ELF3 regulates
epithelial integrity
and hostimmuneresponses
and appears
to function asa tumorELF3 regulates
epithelialintegrity
andhostimmune
responses
andappears tosuppressor in biliary tract cancer.
function as a tumor suppressor in biliary tract cancer.

▍ Background & Results
ELF3 belongs to the E26 transformation-specific family of transcription factors, which plays crucial role in the regulation of homeostasis in epithelial tissues. We had identified ELF3 with lossof-function mutations as a novel driver gene in approximately 11%of ampullary carcinomas, implying that it has an inherent tumorof ELF3 induces the disassembly of cell-cell junctions.
ofLossELF3induces the disassembly of cell-cell junctions.
Figure 2: Loss図２:
Ultrastructural examination by transmission electron microscopy showed an increased abundance ofsuppressor role. Conversely, the amplification and overexpressionmicrovilli in monolayer cultures of ELF3-deficient cells, with fewer cell-cell junctions compared to wildUltrastructuraltype
examination
by transmission electron microscopy showed ancells. Arrowheads indicate cell-cell junctions. Scale bars, 5 µm.
of ELF3 have been reported in breast, prostate, colorectal, andincreased abundance of microvilli in monolayer cultures of ELF3-deficient cells,lung cancers. Hence, further studies are needed to resolve thiswith fewer cell-cell junctions compared to wild-type cells. Arrowheads indicate
apparent contradiction. In the present study, we investigated thecell-cell junctions. Scale bars, 5 µm.
tumor suppressive role of ELF3 in normal bile duct epithelial cells,
and identified novel direct ELF3 targets through a combination主要図表
ofHost immune-related genes
ChIP-Seq and comprehensive transcriptome analyses. Our results
ALOX5Control (Tamoxifen -)ELF3 activation (Tamoxifen +)CXCL1615000
1500
indicate that ELF3 is required for the maintenance of epithelial mor**
**
10000
1000
phology via the direct negative regulation of ZEB2 and the positive
500
5000
regulation of cingulin in bile duct cells. ELF3 also directly up-regu00++
lates the expression of 5-lipoxygenase and CXCL16, and ELF3-deCell adhesion-related genes
ficient cells may escape the attention of immune cells. These findOCLN
CGN
CGN
200
ings suggest that the loss of ELF3 is implicated as a driving force
**
**
150
for early-onset and progression of disease with epithelial-mesen100
550
chymal transition through dampening of host immune defenses in0++
the initial stages of tumor development.
1500% of control

100050000Tamoxifen

500500Tamoxifen

200400400% of control

150300300

100200200

10010050000▍ Significance of the research and Future perspective

H&E

5000

Vimentin% of control

15000

10000

% of control

Life science

Abstract

Tamoxifen

Tamoxifen

ELF3 activation
changes
expression
ofinELF3-related
図３: ELF3
changes expressionof ELF3-related
genes
xenograft tumor. genes in xenoFigure
3:activation(Left) The elevated expression of ELF3 target genes, ALOX5 (encoding 5-lipoxygenase), CXCL16 (encodinggrafttumor.
C-X-C motif chemokine ligand 16), OCLN (encoding occludin) and CGN (encoding cingulin), was observed in
ELF3-/- EMR ELF3-ERT2
xenograft(Right)
The tubular
structure withlosstamoxifen-treated
HBDEC2(Left)
The elevatedexpressionof ELF3targettumors.
genes,ALOX5(encoding
5-lipoxELF3 regulates epithelial integrity and host immune responsesof vimentin was apparently increased in ELF3-activating xenograft tumors.
ygenase),CXCL16 (encoding C-X-C motif chemokine ligand 16), OCLN (encodand functions as a tumor suppressor in biliary tract cancer. Recenting occludin) and CGN (encoding cingulin), was observed in tamoxifen-treatedly, ELF3 and cofactors were identified as an oncogenic super-enHBDEC2ELF3-/- EMR ELF3-ERT2 xenograft tumors. (Right) The tubular structure withhancer in esophageal adenocarcinomas, which strongly drives on⼤学公式サイトResOU掲載
loss of vimentin was apparently increased in ELF3-activating xenograft tumors.

P a t e n t
Suzuki, Masami; Saito-Adachi, Mihoko; Arai, Yasuhito et al. E74-like factor is a key regulator of epithelial integrity and immune response genes in biliary
tract cancer. Cancer Research. 2021; 82(2): 489-500. doi: 10.1158/0008-5472.CAN-19-2988
Yachida, Shinichi; D, Wood, Laura; Suzuki, Masami et al. Genomic Sequencing identifies ELF3 as a driver of ampullary carcinoma. Cancer Cell. 2016;29(2): 229-240. doi: 10.1016/j.ccell.2015.12.012
URL http://www.cgi.med.osaka-u.ac.jp/index.html
K e y w o r d ELF3, transcription factor, cancer
Tr e a t i s e