TY - JOUR
T1 - Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer
AU - Xiong, Xunhao
AU - Rao, Geeta
AU - Roy, Ram Vinod
AU - Zhang, Yushan
AU - Means, Nicolas
AU - Dey, Anindya
AU - Tsaliki, Martha
AU - Saha, Sounik
AU - Bhattacharyya, Sanjib
AU - Dhar Dwivedi, Shailendra Kumar
AU - Rao, Chinthalapally V.
AU - McCormick, Daniel J.
AU - Dhanasekaran, Danny
AU - Ding, Kai
AU - Gillies, Elizabeth
AU - Zhang, Min
AU - Yang, Da
AU - Bhattacharya, Resham
AU - Mukherjee, Priyabrata
N1 - Funding Information:
We would like to thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant. An Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103639 supports the Histology and Immunohistochemistry Core, which provided immunohistochemistry and image analysis services. This research was also supported by Peggy and Charles Stephenson Endowed Chair fund to PM. This work was supported by the National Institutes of Health Grants 2CA136494, CA213278, CA220237 to PM Research reported in this publication was supported in part by the Oklahoma Tobacco Settlement Endowment Trust awarded to the University of Oklahoma/Stephenson Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Oklahoma Tobacco Settlement Endowment Trust. Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225500 awarded to the University of Oklahoma Stephenson Cancer Center and used the Biostatistics and Research Design Shared Resource and the Office of Cancer Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We would like to thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant. An Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103639 supports the Histology and Immunohistochemistry Core, which provided immunohistochemistry and image analysis services. This research was also supported by Peggy and Charles Stephenson Endowed Chair fund to PM. This work was supported by the National Institutes of Health Grants 2CA136494, CA213278, CA220237 to PM Research reported in this publication was supported in part by the Oklahoma Tobacco Settlement Endowment Trust awarded to the University of Oklahoma/Stephenson Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Oklahoma Tobacco Settlement Endowment Trust. Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225500 awarded to the University of Oklahoma Stephenson Cancer Center and used the Biostatistics and Research Design Shared Resource and the Office of Cancer Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.
AB - Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.
KW - KRAS
KW - UBAP2
KW - macropinocytosis
KW - pancreatic cancer
KW - small GTPases
KW - therapeutic target
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UR - http://www.scopus.com/inward/citedby.url?scp=85088240901&partnerID=8YFLogxK
U2 - 10.1096/fj.201902826RR
DO - 10.1096/fj.201902826RR
M3 - Article
C2 - 32692445
AN - SCOPUS:85088240901
SN - 0892-6638
VL - 34
SP - 12024
EP - 12039
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -