RESUMO
Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer.
Assuntos
Aciltransferases , Carcinoma Ductal Pancreático , Regulação Neoplásica da Expressão Gênica , Lipoilação , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-myc , Animais , Feminino , Humanos , Masculino , Camundongos , Aciltransferases/metabolismo , Aciltransferases/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Estabilidade de RNA , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de SinaisRESUMO
Hepatocellular carcinoma is the prevailing malignant neoplasm affecting the liver, often diagnosed at an advanced stage and associated with an unfavorable overall prognosis. Sorafenib and Lenvatinib have emerged as first-line therapeutic drugs for advanced hepatocellular carcinoma, improving the prognosis for these patients. Nevertheless, the issue of tyrosine kinase inhibitor (TKI) resistance poses a substantial obstacle in the management of advanced hepatocellular carcinoma. The pathogenesis and advancement of hepatocellular carcinoma exhibit a close association with metabolic reprogramming, yet the attention given to lipid metabolism dysregulation in hepatocellular carcinoma development remains relatively restricted. This review summarizes the potential significance and research progress of lipid metabolism dysfunction in Sorafenib and Lenvatinib resistance in hepatocellular carcinoma. Targeting hepatocellular carcinoma lipid metabolism holds promising potential as an effective strategy to overcome hepatocellular carcinoma drug resistance in the future.
RESUMO
Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver cancer progression and fills the research gap in non-histone protein crotonylation function.
Assuntos
Neoplasias Hepáticas , Lisina , Desacetilase 6 de Histona/metabolismo , Histonas/metabolismo , Humanos , Hipóxia , Lamina Tipo A/metabolismo , Neoplasias Hepáticas/genética , Lisina/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Cartilage formation during both embryonic development and bone repairing processes involves mesenchymal stem cells (MSCs) differentiation. Wnt/ß-catenin signaling pathway inhibits early chondrogenesis and is down-regulated during Transforming growth factor-ß1 (TGF-ß1)-induced chondrogenesis. However, the regulatory molecules that participate in the process is unknown. This study was designed to investigate the underlying mechanisms that down-regulate Wnt/ß-catenin pathway during chondrogenesis. TGF-ß1-induced micromass cultures of C3H10T1/2 were used as chondrocyte differentiation model. Gene expression profile was detected by realtime-PCR. Regulatory role of HDAC1 on ß-catenin was investigated by luciferase assay, chromatin immunoprecipitation (ChIP) assay, co-immunoprecipitation (Co-IP) assay and in vitro ubiquitination assay. In this study, we showed that HDAC1 was induced and suppressed ß-catenin gene expression through direct binding to its promoter. Besides, HDAC1 could also interact with deacetylate ß-catenin protein through its deacetylase domain, which causes degradation of ß-catenin. Our results indicate that HDAC1 plays an important role in chondrogenesis and may represent a therapeutic target for modulation of cartilage development.