NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response.

Yong-Qiang Hua,Wei-dong Shi,Ke Zhang,Zhou-Yu Ning,Jie Sheng,Ye Li,Lu-Ming Liu

doi:10.3389/fcell.2021.641836

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient prognosis. A cellular stress response mechanism called the unfolded protein response (UPR) has been implicated in PDAC progression. More recently, nucleobindin 1 (NUCB1), a calcium-binding protein, has been shown to control the UPR but its precise role in PDAC has not been explored. Here, we found that downregulation of NUCB1 was associated with poor prognosis in patients with PDAC. Functionally, NUCB1 overexpression suppressed pancreatic cancer cell proliferation and showed additive effects with gemcitabine (GEM) in vitro and in vivo. Moreover, by controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. Last but not least, we uncovered METTL3-mediated m6A modification on NUCB1 5′UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. Taken together, our study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells and identified METTL3-mediated m6A modification as a mechanism for NUCB1 downregulation in PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is responsible for more than 90% of all pancreatic diseases and is a highly devastating cancer with poor clinical prognosis (Kleeff et al, 2016; Orth et al, 2019)
While CCDC88A, CCDC88C, and NUCB2 expression did not correlate with prognosis in PAAD patients (Figures 1A–C), low expression of nucleobindin 1 (NUCB1) was highly associated with lower patient survival rate (Figure 1C)
We provided evidence for a role of NUCB1 in regulating proliferation and the anti-tumor effects of gemcitabine in pancreatic cancer cells, and proposed a mechanism whereby METTL3 controls NUCB1 expression, which modulates ATF activity and subsequently controls the unfolded protein response (UPR) (Figure 7)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is responsible for more than 90% of all pancreatic diseases and is a highly devastating cancer with poor clinical prognosis (Kleeff et al, 2016; Orth et al, 2019). Several risk factors are associated with PDAC, including obesity and type-2 diabetes (Calle et al, 2003; Rahn et al, 2018), as well as lifestyle habits such as smoking and alcohol consumption (Blot et al, 1988). Prognosis for PDAC patients is highly determined by disease stage at the time of diagnosis, and the lack of early detection tools presents a major challenge in improving clinical outcomes for PDAC patients. Surgical resection followed by adjuvant chemotherapy serves as a current treatment strategy, only a very small percentage (10–20%) of PDAC patients present early-stage

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Conclusion