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KAT7 promotes radioresistance through upregulating PI3K/AKT signaling in breast cancer
Yan Ma1,2, Xiaohua Chen2, Ting Ding3
1The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, 730000, P. R. China.
Abstract:
Chromatin-modifying enzymes are commonly altered in cancers, but the molecular mechanism by which they regulate cancers remains poorly understood. Herein, we demonstrated that Lysine acetyltransferase 7 (KAT7) was upregulated in breast cancer. KAT7 expression negatively correlated with the survival of breast cancer patients, and KAT7 silencing suppressed breast cancer radioresistance in vitro. Mechanistically, KAT7 activated Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) transcription, leading to enhanced PI3K/AKT signaling and radioresistance. Overexpression of AKT or PIK3CA restored radioresistance suppression induced by KAT7 inhibition. Moreover, overexpression of KAT7, but not KAT7 acetyltransferase activity-deficient mutants promoted AKT phosphorylation at the Ser473 site, PIK3CA expression and radioresistance suppression due to KAT7 inhibition. In conclusion, KAT7 has huge prospects for clinical application as a new target for predicting radioresistance in breast cancer patients.
Insights
Lysine acetyltransferase 7 (KAT7) promotes breast cancer radioresistance by upregulating PIK3CA and activating PI3K/AKT signaling. Targeting KAT7 may improve predicting and treating radioresistant breast cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chromatin-modifying enzymes play crucial roles in cancer development, but their precise mechanisms are often unclear.
- Lysine acetyltransferase 7 (KAT7) alterations are implicated in various cancers, necessitating further investigation into its role in breast cancer progression.
Purpose of the Study:
- To elucidate the molecular mechanism by which KAT7 influences breast cancer radioresistance.
- To evaluate KAT7 as a potential predictive biomarker and therapeutic target for radioresistant breast cancer.
Main Methods:
- Quantitative analysis of KAT7 expression in breast cancer tissues.
- In vitro experiments involving KAT7 silencing and overexpression in breast cancer cell lines.
- Assessment of PIK3CA transcription, PI3K/AKT signaling pathway activation, and radioresistance levels.
- Utilizing KAT7 acetyltransferase activity-deficient mutants to discern the role of enzymatic activity.
Main Results:
- KAT7 expression was significantly upregulated in breast cancer and correlated with poorer patient survival.
- KAT7 silencing markedly reduced breast cancer cell radioresistance in vitro.
- KAT7 was found to activate Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) transcription, thereby enhancing PI3K/AKT signaling and promoting radioresistance.
- Overexpression of AKT or PIK3CA rescued the radioresistance defect caused by KAT7 inhibition, confirming the pathway's importance.
- KAT7's enzymatic activity, not just its presence, was crucial for promoting AKT phosphorylation, PIK3CA expression, and radioresistance.
Conclusions:
- KAT7 plays a critical role in promoting breast cancer radioresistance through the PIK3CA/PI3K/AKT signaling pathway.
- KAT7 represents a promising therapeutic target for overcoming radioresistance in breast cancer patients.
- KAT7 expression levels may serve as a valuable biomarker for predicting radioresistance in breast cancer.
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