首页|Elevated FBXL6 activates both wild-type KRAS and mutant KRAS G12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice
Elevated FBXL6 activates both wild-type KRAS and mutant KRAS G12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice
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Background:Kirsten rat sarcoma(KRAS)and mutant KRAS G12D have been implicated in human cancers,but it remains unclear whether their activation requires ubiquitination.This study aimed to investigate whether and how F-box and leucine-rich repeat 6(FBXL6)regulates KRAS and KRAS G12D activity in hepatocellular carcinoma(HCC).Methods:We constructed transgenic mouse strains LC(LSL-Fbxl6KI/+;Alb-Cre,n=13),KC(LSL-KrasG12D/+;Alb-Cre,n=10)and KLC(LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre,n=12)mice,and then monitored HCC for 320d.Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation.Co-immunoprecipitation(Co-IP),Western blotting,ubiquitination assay,and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS.The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase(ERK)/mammalian target of rapamycin(mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2(PRELID2)axis was evaluated in 129 paired samples from HCC patients.Results:FBXL6 is highly expressed in HCC as well as other human cancers(P＜0.001).Interestingly,FBXL6 drives HCC in transgenic mice.Mechanistically,elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRAS G12D at lysine 128,leading to the activation of both KRAS and KRAS G12D and promoting their binding to the serine/threonine-protein kinase RAF,which is followed by the activation of mitogen-activated protein kinase kinase(MEK)/ERK/mTOR signaling.The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2,which induces reactive oxygen species(ROS)generation.Furthermore,hepatic FBXL6 upregulation facilitates KRAS G12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis.Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo.In clinical samples,FBXL6 expression positively correlates with p-ERK(x2=85.067,P＜0.001),p-mTOR(x2=66.919,P＜0.001)and PRELID2(x2=20.891,P＜0.001).The Kaplan-Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival(log-rank P＜0.001).Conclusions:FBXL6 activates KRAS or KRAS G12D via ubiquitination at the site K128,leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis.Dual inhibition of MEK and mTOR effectively protects against FBXL6-and KRAS G12D-induced tumorigenesis,providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer.
UbiquitinationKirsten rat sarcoma(KRAS)F-box and leucine-rich repeat 6(FBXL6)PRELID2Reactive oxygen speciesExtracellular signal-regulated kinase(ERK)Mammalian target of rapamycin
Key Laboratory of Hepatobiliary and Pancreatic Surgery,Institute of Hepatobiliary Surgery,Southwest Hospital,Army Medical University,Chongqing 400038,China
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