Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer
Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep...
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Published in | Experimental & molecular medicine Vol. 55; no. 10; pp. 2220 - 2237 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Springer Nature B.V
01.10.2023
Nature Publishing Group UK Nature Publishing Group 생화학분자생물학회 |
Subjects | |
Online Access | Get full text |
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Summary: | Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRAS
-Raf-MEK-c-Myc axis in KRAS
lung cancer cells and in lung tumors of a mouse model with spontaneous Kras
expression. KRAS
-induced SIRT1 bound to KRAS
and stably deacetylated KRAS
at lysine 104, which increased KRAS
activity. SIRT1 knockdown (K/D) or the SIRT1
mutation increased KRAS
acetylation, which decreased KRAS
activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in Kras
;Sirt1
mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-Kras
;Sirt1
mice and mice in each single-drug treatment group. Then, we identified p300 as a KRAS
acetyltransferase that reinforced KRAS
lysine 104 acetylation and robustly decreased KRAS
activity. KRAS
lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRAS
activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRAS
mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRAS
lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRAS
lung cancer patients. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2092-6413 1226-3613 2092-6413 |
DOI: | 10.1038/s12276-023-01091-0 |