Abstract
Pancreatic cancer (PC) is an aggressive malignancy associated with a poor prognosis and low responsiveness to chemotherapy and radiotherapy. 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.
Highlights
IntroductionThe incidence and mortality of Pancreatic cancer (PC) have decreased in recent years, it is an aggressive malignancy with a 5-year relative survival rate of 8% [2]
Pancreatic cancer (PC) is the fourth leading cause of cancer-related death worldwide [1]
We examined the role of Sox6 in PC development and progression in vitro and in vivo and elucidated a potential regulatory mechanism involving the transcription factor Twist1 and the Akt signalling pathway
Summary
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% [2]. 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 [3,4,5]. PC metastasis and treatment resistance have been associated with EMT, a process by which polarized epithelial cells acquire a mesenchymal phenotype characterized by increased migratory capacity, invasiveness and resistance to apoptosis [6, 7]. 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 [9,10,11]. EMT is induced by the basic helix–loop–helix transcription factor Twist, which acts together with the zinc-finger transcription factor Snail to repress the a 2018 The Authors
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