USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

Abstract

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

Insights Into the Properties, Biological Functions, and Regulation of USP21

“…Although several microtubule-associated proteins, such as MARKs and CKAP5, were also identified as interacting partners of USP21, USP21 knockdown did not affect the expression and ubiquitylation levels of these proteins ( Urbe et al, 2012 ). However, later studies demonstrated that USP21 could regulate YAP transcriptional activity and cytoskeleton-based cellular process macropinocytosis by regulating the stability and ubiquitylation of MARKs ( Nguyen et al, 2017 ; Hou et al, 2021 ). To our knowledge, sever other DUBs, including CYLD, UCHL1, and BRCC36, have also been identified to be associated with microtubules, establishing the links between deubiquitylation modification and microtubule cell biology ( Stegmeier et al, 2007 ; Gao et al, 2008 ; Bheda et al, 2010 ; Yan et al, 2015 ).…”

“…Recently, USP21 has been authenticated as a frequently amplified gene in pancreatic ductal adenocarcinoma (PDAC) with the capacity to enhance PDAC cell stemness by stabilizing TCF7 ( Hou et al, 2019 ). Using the inducible Kras G12D / Trp53 −/− PDAC mouse model, the same group subsequently identified that USP21 supported the growth of oncogenic KRAS-independent PDAC by elevating MARK3-mediated macropinocytosis ( Hou et al, 2021 ). Together, these two studies prompted the evaluation of USP21 as a novel therapeutic target, as well as a potential genetic factor that may affect responsiveness to emerging KRAS inhibitors in patients with PDAC ( Crawford, 2021 ).…”

The Role and Therapeutic Potential of Macropinocytosis in Cancer

“…This process depends on the activation of the RAS gene, growth factor receptors (GFRs), and other signal pathways ( Hesketh et al, 2020 ; Hobbs et al, 2020 ). KRAS-transformed pancreatic cancer cells activate macropinocytosis to absorb and degrade extracellular fluids in order to survive ( Hou et al, 2021 ). Membrane localization of trafficking syndecan-1 (SDC1) has been shown to be an essential mechanism for promoting macropinocytosis and sustaining the uncontrolled growth of oncogenic KRAS-driven pancreatic ductal adenocarcinoma (PDAC).…”

Loss of Heterozygosity for KrasG12D Promotes Malignant Phenotype of Pancreatic Ductal Adenocarcinoma by Activating HIF-2α-c-Myc-Regulated Glutamine Metabolism

“…Current studies indicate that pancreatic cancer is mainly regulated by tumor-suppressor gene inactivation and oncogene activation [ 7 ]. The KRAS gene is one of the most frequently mutated oncogenes in many cancers, and can be found in nearly all PDAC cases [ 8 , 9 , 10 ]. KRAS belongs to a class of genes that encodes guanosine triphosphatase and regulates downstream signaling pathways through growth factor receptors [ 11 ].…”