Abstract
Speckle-type POZ domain protein (SPOP), an adaptor in the E3 ubiquitin ligase complex, recognizes substrates and promotes protein degradation via the ubiquitin-proteasome system. It appears to help regulate progression of several cancers, and we show here that it acts as a tumor suppressor in pancreatic cancer. Our analysis of patient tissues showed decreased SPOP expression, which was associated with poor prognosis. SPOP knockdown in SW1990 (in vitro/vivo) and PANC-1 (in vitro) cells led to significantly greater proliferation, migration, and invasion. Co-immunoprecipitation experiments in SW1990 cells showed that SPOP interacted with the stem-cell marker NANOG, and this interaction has recently been shown to play a critical role in regulating progression of prostate cancer. We showed that, in one patient with pancreatic cancer, the expression of a truncated form of SPOP (p.Q360*) lacking the nuclear localization signal led to nuclear accumulation of NANOG, which promoted growth and metastasis of pancreatic cancer cells. Our results suggest that SPOP suppresses progression of pancreatic cancer by promoting the ubiquitination and subsequent degradation of NANOG. These results identify the SPOP-NANOG interaction as a potential therapeutic target against pancreatic cancer.
Highlights
Pancreatic cancer is characterized by poor prognosis and high mortality
Low expression of Speckle-type POZ domain protein (SPOP) correlates with poor prognosis in pancreatic cancer A total of 21 pancreatic ductal adenocarcinoma tissues and adjacent non-tumor tissues were assayed for SPOP levels using western blotting (WB) and immunohistochemistry
It was downregulated in most pancreatic cancer patients in our study, and low SPOP expression correlated with poor prognosis
Summary
Pancreatic cancer is characterized by poor prognosis and high mortality. In 2018, an estimated 458,000 new cases of pancreatic cancer and 432,000 deaths related to the disease were recorded worldwide[1]. The length and type of ubiquitination affect the fate of the protein[4,5]
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