Wei Zhao1, Huanye Mo2, Runkun Liu2, Tianxiang Chen2, Nan Yang3, Zhikui Liu4. 1. Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, 710061, Xi'an, China. 2. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, 710061, Xi'an, China. 3. Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, 710061, Xi'an, China. nan_yang@xjtufh.edu.cn. 4. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, 710061, Xi'an, China. liuzk0319@xjtufh.edu.cn.
Abstract
BACKGROUND: Lysine acetyltransferase 6 A (KAT6A) is a MYST-type histone acetyltransferase (HAT) enzyme, which contributes to histone modification and cancer development. However, its biological functions and molecular mechanisms, which respect to hepatocellular carcinoma (HCC), are still largely unknown. METHODS: Immunohistochemical, western blot and qRT-PCR analysis of KAT6A were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of KAT6A in the progression of HCC. RESULTS: We demonstrated that KAT6A expression was upregulated in HCC tissues and cell lines. Clinical analysis showed that increased KAT6A was significantly associated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that KAT6A promoted cell viability, proliferation and colony formation of HCC cells in vitro and in vivo. We confirmed that KAT6A acetylates lysine 23 of histone H3 (H3K23), and then enhances the association of the nuclear receptor binding protein TRIM24 and H3K23ac. Consequently, TRIM24 functions as a transcriptional activator to activate SOX2 transcription and expression, leading to HCC tumorigenesis. Restoration of SOX2 at least partially abolished the biological effects of KAT6A on HCC cells. Overexpression of KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac binding sites did not affect SOX2 expression and HCC biological function. Moreover, matrix stiffness can upregulate the expression of KAT6A in HCC cells. CONCLUSIONS: Our data support the first evidence that KAT6A plays an oncogenic role in HCC through H3K23ac/TRIM24-SOX2 pathway, and represents a promising therapeutic strategy for HCC patients.
BACKGROUND: Lysine acetyltransferase 6 A (KAT6A) is a MYST-type histone acetyltransferase (HAT) enzyme, which contributes to histone modification and cancer development. However, its biological functions and molecular mechanisms, which respect to hepatocellular carcinoma (HCC), are still largely unknown. METHODS: Immunohistochemical, western blot and qRT-PCR analysis of KAT6A were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of KAT6A in the progression of HCC. RESULTS: We demonstrated that KAT6A expression was upregulated in HCC tissues and cell lines. Clinical analysis showed that increased KAT6A was significantly associated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that KAT6A promoted cell viability, proliferation and colony formation of HCC cells in vitro and in vivo. We confirmed that KAT6A acetylates lysine 23 of histone H3 (H3K23), and then enhances the association of the nuclear receptor binding protein TRIM24 and H3K23ac. Consequently, TRIM24 functions as a transcriptional activator to activate SOX2 transcription and expression, leading to HCC tumorigenesis. Restoration of SOX2 at least partially abolished the biological effects of KAT6A on HCC cells. Overexpression of KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac binding sites did not affect SOX2 expression and HCC biological function. Moreover, matrix stiffness can upregulate the expression of KAT6A in HCC cells. CONCLUSIONS: Our data support the first evidence that KAT6A plays an oncogenic role in HCC through H3K23ac/TRIM24-SOX2 pathway, and represents a promising therapeutic strategy for HCC patients.
Authors: Brittany Turner-Ivey; Stephen T Guest; Jonathan C Irish; Christiana S Kappler; Elizabeth Garrett-Mayer; Robert C Wilson; Stephen P Ethier Journal: Neoplasia Date: 2014-08 Impact factor: 5.715