Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression.
Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary, our results identify CUL3-KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis and demonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Cen
C
Zhang
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Juan
J
Liu
Nelson Institute of Environmental Medicine, New York University School of Medicine, New York University, Tuxedo, New Jersey 10987, USA;
Grace
G
Huang
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Yuhan
Y
Zhao
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Xuetian
X
Yue
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Hao
H
Wu
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Jun
J
Li
Nelson Institute of Environmental Medicine, New York University School of Medicine, New York University, Tuxedo, New Jersey 10987, USA;
Junlan
J
Zhu
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Zhiyuan
Z
Shen
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Bruce G
BG
Haffty
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
Wenwei
W
Hu
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Pharmacology, Rutgers University, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Zhaohui
Z
Feng
D000072283:A549 Cells; D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008807:Mice, Inbred BALB C; D059748:Proteolysis
C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C000620120:KLHL25 protein, human; D008055:Lipids; D001275:ATP Citrate (pro-S)-Lyase
ACLY; CUL3; KLHL25; lipid synthesis; tumor progression; ubiquitination
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