USP44 suppresses pancreatic cancer progression and overcomes gemcitabine resistance by deubiquitinating FBP1
Authors: Sisi Deng
Shikai Zhu
Hongji Yang
Chong Yang
Ping Fan
Mi Li
Xin Jin
Journal: American journal of cancer research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Fructose-1,6-bisphosphatase; chemotherapy resistance; deubiquitination; gemcitabine; pancreatic cancer
Affiliations: Organ Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 610072, China., Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China., Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.

Abstract:  Pancreatic ductal adenocarcinoma (PDAC) is considered to be the deadliest cancer type in the world. Chemotherapy resistance, including gemcitabine, is the main reason for poor prognosis in PDAC patients. Increased aerobic glycolysis is involved in chemotherapy resistance in PDAC. Fructose-1,6-bisphosphatase (FBP1) is one of the key enzymes in the process of gluconeogenesis and negatively regulates aerobic glycolysis. FBP1 loss is common in PDAC patient specimens and is associated with gemcitabine resistance by activating the MAPK pathway. While the regulatory mechanism of FBP1 in pancreatic cancer remains un-elucidated. Here, we found that ubiquitin-specific protease 44 (USP44) was down-regulated in PDAC patients, and USP44 might be a prognostic marker for PDAC patients. USP44 inhibit tumor cells progression and regulated gemcitabine resistance in PDAC. Importantly, we revealed USP44 promoted FBP1 deubiquitination to increase FBP1 protein expression in pancreatic cancer, which might be one of the underlying mechanisms of USP44 impeding the progression of pancreatic cancer. Collectively, the recognition of USP44 in the stabilization of FBP1 indicates USP44 might be considered as a new prognostic marker for pancreatic cancer therapy. 

Retracted: No

PubPeer comments:
 1. In figure 1A, IHC of USP44 in tumor tissues presented extremely low expression; however, in figure 4A, IHC of USP in tumor tissues seems to be significantly positive with high expression. It s unbelievable.  Figure 1A  Figure 4A 2. For figure 1E, the article depicted that we analyzed whether USP44 was associated with the prognosis of PDAC patients through The Human Protein Atlas dataset, and found that USP44 down-regulation was negatively correlated with prognosis in pancreatic cancer patients (Figure 1E) . However, via The Human Protein Atlas, the results of survival analysis for USP44 indicate that USP44 is not prognostic in pancreatic cancer. How could the authors draw this conclusion of negative correlation with prognosis in PDAC?  Figure 1E Online Analysis in The Human Protein Atlas: https: www.proteinatlas.org ENSG00000136014-USP44 pathology pancreatic+cancer 3. In figure 2A 2B 2I, IC50 for almost all groups could not match with the plotted curve. For instance, in Figure 2B, IC50 for pcDNA3.1 was only 2.99+ -0.93 uM, as the author indicated in the figure; however, it is obviously larger than 3 and close to 10, judged by the plotted curve. All IC50 results were not credible.  Figure 2A 2B  Figure 2I 4. In figure 2C 2D, the author explored the effect of USP44 on glucose consumption and lactate production, base on a reference published on Carcinogenesis in 2014. However, this reference has been retracted by Carcinogenesis in 2019, due to image manuplation. How could we believe the results which based on a false reference?  The article indicated ref [19] as the basis of figure 2C 2D  Ref [19] has been retracted due to image manuplation PubPeer linkage: https: pubpeer.com publications AEC7639F85BEC0B96B1BB14E0E6BA8 , 
 #1 Xin Jin Response:        , 
 #1          ,