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Snail acetylation by autophagy-derived acetyl-coenzyme A promotes invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells

 Jang Hee Han  ;  Yong Keon Kim  ;  Hakhyun Kim  ;  Jooyoung Lee  ;  Myung Joon Oh  ;  Sang Bum Kim  ;  Minjee Kim  ;  Kook Hwan Kim  ;  Hyun Ju Yoon  ;  Myung-Shik Lee  ;  John D Minna  ;  Michael A White  ;  Hyun Seok Kim 
 CANCER COMMUNICATIONS, Vol.42(8) : 716-749, 2022-08 
Journal Title
Issue Date
AMP-Activated Protein Kinases / metabolism* ; Acetyl Coenzyme A / pharmacology ; Acetylation ; Animals ; Autophagy / genetics ; Lung Neoplasms* / genetics ; Mammals ; Mice ; Neoplastic Processes ; Proto-Oncogene Proteins p21(ras)* / genetics ; Snail Family Transcription Factors / metabolism* ; Transcription Factors / genetics
ACLY ; CAMKK2 ; KRAS inhibitor ; acetyl-coenzyme A ; acetyl-snail ; autophagy ; epithelial-to-mesenchymal transition ; metastasis ; non-small-cell lung cancer ; pancreatic cancer ; snail
Background: Autophagy is elevated in metastatic tumors and is often associated with active epithelial-to-mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT.

Methods: We employed a liquid chromatography-based metabolomic approach with kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1) gene co-mutated (KL) cells that represent an autophagy/EMT-coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-driven EMT activation were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein-green fluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif-driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system.

Results: We found that autophagy in KL cancer cells increased acetyl-coenzyme A (acetyl-CoA), which facilitated the acetylation and stabilization of the EMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in tumor tissues and in autophagy-activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro-metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo.

Conclusions: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetyl-CoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Kook Hwan(김국환)
Kim, Sang Bum(김상범) ORCID logo https://orcid.org/0000-0001-5965-3354
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Lee, Joo Young(이주영)
Han, Jang Hee(한장희)
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