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Crotonylomics sequencing of human non small cell lung cancer cell lines

ABSTRACT: Crotonylation is a crotonyl-coenzyme A (CoA)-mediated post-translational modification best known for its roles in epigenetic regulation. Histone lysine crotonylation (Kcr) has been reported to be involved in tumor-related biological functions such as DNA damage repair and immune infiltration. Here we find that abnormal reduction of histone Kcr significantly correlates with a poor response to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in in-house-established drug-resistant models of lung cancer cell lines, and in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. The crotonyl-CoA-producing enzyme ACSS2 is the key regulator of the resistance-related change of crotonylation. Quantitative crotonylomic, transcriptomic and epigenomic analyses reveal that EGFR-TKI resistance is accompanied by reduced levels of histone 3 lysine 56 crotonylation (H3K56cr) on chromatin, which inhibits transcription of HNF1A and activates the PI3K/AKT signaling pathway. Studies of patient-derived organoids (PDOs) and resistant lung cancer CDX and PDX models treated with a novel histone decrotonylase (HDCR) inhibitor, S67, demonstrate that up-regulation of H3K56cr sensitizes cells to the effect of EGFR-TKIs. These findings uncover the role of histone Kcr in resistance to EGFR-TKIs and suggest a new combination therapy in lung cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: sihong chen

LAB HEAD: sihong chen

PROVIDER: PXD053030 | Pride | 2025-09-22

REPOSITORIES: Pride

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			Action	DRS
	DE301LPCrB1_HCC827_Er_OE-ACSS2_Slot1-41_1_2381.d.zip	Other
	DE301LPCrB1_HCC827_Er_Slot1-42_1_2383.d.zip	Other
	DE301LPCrB1_HCC827_Slot1-43_1_2385.d.zip	Other
	txt.zip	Other

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Project description:Crotonylation is a crotonyl-coenzyme A (CoA)-mediated post-translational modification best known for its roles in epigenetic regulation. Histone lysine crotonylation (Kcr) has been reported to be involved in tumor-related biological functions such as DNA damage repair and immune infiltration. Here we find that abnormal reduction of histone Kcr significantly correlates with a poor response to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in resistant models of lung cancer cell lines, and in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. The crotonyl-CoA-producing enzyme ACSS2 is the key regulator of the resistance-related change of crotonylation. Quantitative crotonylomic, transcriptomic and epigenomic analyses reveal that EGFR-TKI resistance is accompanied by reduced levels of histone 3 lysine 56 crotonylation (H3K56cr) on chromatin, which inhibits transcription of HNF1A and activates the PI3K/AKT signaling pathway.

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