Identiﬁcation of Sox6 as a regulator of pancreatic cancer
a, b, #
, Qiongying Yuan
, Yuanye Jiang
, Li huang
, Congying Chen
, Rong Wan
*, Xingpeng Wang
, Lijuan Yang
Department of Gastroenterology, School of Medicine, Shanghai General Hospital/First People’s Hospital, Shanghai Jiao Tong
University, Shanghai, China
Shanghai Key Laboratory of Pancreatic Disease, School of Medicine, Institute of Pancreatic Disease, Shanghai Jiao Tong
University, Shanghai, China
Department of Gastroenterology, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
Department of Gastroenterology, The Central Hospital of Putuo District, Shanghai University of Traditional Chinese Medicine,
Received: April 5, 2017; Accepted: October 26, 2017
Pancreatic cancer (PC) is an aggressive malignancy associated with a poor prognosis and low responsiveness to chemotherapy and radiother-
apy. Most patients with PC have metastatic disease at diagnosis, which partly accounts for the high mortality from this disease. Here, we
explored the role of the transcription factor sex-determining region Y-box (Sox) 6 in the invasiveness of PC cells. We showed that Sox6 is
down-regulated in patients with PC in association with metastatic disease. Sox6 overexpression suppressed PC cell proliferation and migration
in vitro and tumour growth and liver metastasis in vivo. Sox6 inhibited epithelial-mesenchymal transition (EMT), and Akt signalling. Sox6 was
shown to interact with the promoter of Twist1, a helix–loop–helix transcription factor involved in the induction of EMT, and to modulate the
expression of Twist1 by recruiting histone deacetylase 1 to the promoter of the Twist1 gene. Twist1 overexpression reversed the effect of Sox6
on inhibiting EMT, conﬁrming that the effect of Sox6 on suppressing tumour invasiveness is mediated by the modulation of Twist1 expression.
These results suggest a novel mechanism underlying the aggressive behaviour of PC cells and identify potential therapeutic targets for the
treatment of PC.
PC is the fourth leading cause of cancer-related death worldwide .
Although the incidence and mortality of PC have decreased in recent
years, it is an aggressive malignancy with a 5-year relative survival
rate of 8% . For all stages combined, the 1-year relative survival
rate is only 21%. The high potential of PC cells for invasion and
metastasis is the main cause of its high mortality, and approximately
80% of patients have metastatic disease at diagnosis [3–5]. There-
fore, a better understanding of the molecular mechanism(s) involved
in the aggressive behaviour of PC is essential for the design of effec-
tive treatment strategies for this disease.
PC metastasis and treatment resistance have been associated
with EMT, a process by which polarized epithelial cells acquire a mes-
enchymal phenotype characterized by increased migratory capacity,
invasiveness and resistance to apoptosis [6, 7]. EMT is characterized
by the loss of the expression of the epithelial marker E-cadherin .
PC cells with an EMT phenotype show increased chemoresistance
and cancer stem cell properties, and different growth factors and
transcription factors promote EMT in PC cells [9–11]. EMT is induced
by the basic helix–loop–helix transcription factor Twist1, which acts
together with the zinc-ﬁnger transcription factor Snail to repress the
These authors contributed equally to this work.
*Correspondence to: Rong WAN
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1864-1872