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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
KAT2A affects tumor metabolic reprogramming in colon cancer progression through epigenetic activation of E2F1
1Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100043, People's Republic of China.
Abstract:
Lysine acetyltransferase 2 A (KAT2A) has been implicated in tumorigenesis; nevertheless, the mechanism underlying its tumor-initiating effect remains elusive. In the present study, we aimed to identify the possible role of KAT2A in regulating metabolic reprogramming, a hallmark of cancer, in colon cancer (CC). KAT2A was found to be overexpressed in CC and correlated with metastases. KAT2A induced proliferation, migration, invasion, and epithelial-mesenchymal transition of CC cells, along with elevated cellular glycolytic capacity and mitochondrial stress. Functional enrichment analyses predicted and ChIP assays verified that KAT2A activated E2F transcription factor 1 (E2F1) by modifying the acetylation of H3K9. Rescue experiments revealed that E2F1 downregulation inhibited cellular activity, aerobic glycolysis and mitochondrial respiration in CC in the presence of KAT2A. Moreover, KAT2A/E2F1 promoted tumorigenic activity and lung metastases of CC cells in mice. Taken together, our findings demonstrate the substantial role of KAT2A in the modulation of post-translational modifications of E2F1 in CC, suggesting that knockdown of KAT2A may be a potential strategy for CC treatment.
Insights
Lysine acetyltransferase 2A (KAT2A) drives colon cancer progression by altering cell metabolism and promoting metastasis. Targeting KAT2A may offer a new therapeutic strategy for colon cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Lysine acetyltransferase 2A (KAT2A) is linked to cancer, but its role in colon cancer (CC) initiation and progression is unclear.
- Metabolic reprogramming is a key feature of cancer development.
Purpose of the Study:
- To investigate the role of KAT2A in metabolic reprogramming in colon cancer.
- To elucidate the molecular mechanisms by which KAT2A influences colon cancer progression.
Main Methods:
- Overexpression analysis of KAT2A in CC tissues.
- Assessment of CC cell proliferation, migration, invasion, and epithelial-mesenchymal transition.
- Measurement of cellular glycolysis and mitochondrial function.
- Chromatin immunoprecipitation (ChIP) assays to verify KAT2A binding to E2F1.
- Rescue experiments involving E2F1 downregulation.
- In vivo mouse models for tumorigenesis and metastasis studies.
Main Results:
- KAT2A is overexpressed in CC and associated with metastasis.
- KAT2A enhances CC cell proliferation, migration, invasion, and EMT.
- KAT2A elevates cellular glycolysis and mitochondrial stress.
- KAT2A activates E2F transcription factor 1 (E2F1) via H3K9 acetylation.
- E2F1 downregulation reverses KAT2A-induced metabolic and cellular changes.
- KAT2A/E2F1 signaling promotes tumor growth and lung metastasis in mice.
Conclusions:
- KAT2A plays a significant role in colon cancer progression by modulating E2F1 acetylation and promoting metabolic reprogramming.
- KAT2A/E2F1 axis is crucial for colon cancer cell tumorigenesis and metastasis.
- Targeting KAT2A presents a potential therapeutic strategy for colon cancer.
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