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Cellular and Molecular Biology

Matrix stiffness-induced upregulation of histone acetyltransferase KAT6A promotes hepatocellular carcinoma progression through regulating SOX2 expression

British Journal of Cancer volume 127, pages 202–210 (2022)Cite this article

Subjects

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.

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Fig. 1: KAT6A is frequently overexpressed in HCC tissues and cell lines.
Fig. 2: KAT6A promotes cell viability, proliferation and colony formation of HCC cells in vitro and in vivo.
Fig. 3: KAT6A upregulates SOX2 expression in HCC cells.
Fig. 4: KAT6A acetyltransferase activity is critical for SOX2 expression.
Fig. 5: H3K23 acetylation binds with TRIM24 to mediate SOX2 expression.
Fig. 6: KAT6A is upregulated by high matrix stiffness and mediates its promoting effects.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82103428), Natural Science Basic Research Program of Shaanxi (No.2020JQ-496, No.2020JQ-498); the Institutional Foundation of the First Affiliated Hospital of Xi’an Jiaotong University (2019QN-24, 2020QN-10); the Fundamental Research Funds for the Central Universities (Program No. xzy012020041).

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Authors and Affiliations

  1. Department of General Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, 710061, Xi’an, China

    Wei Zhao

  2. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, 710061, Xi’an, China

    Huanye Mo, Runkun Liu, Tianxiang Chen & Zhikui Liu

  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

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Contributions

Study concept and design: ZKL and NY. Acquisition of the data: WZ, HYM, RKL, TXC and NY. Management of data acquisition: WZ, HYM, RKL, TXC, ZKL and NY. Analysis of the present data: WZ, HYM and ZKL. Statistical analysis: WZ and NY. Critical interpretation of the present data: WZ, HYM, RKL, TXC and NY. Drafting of the paper: WZ, ZKL and NY. Critical revision of the paper for important intellectual content: WZ, HYM, RKL, TXC, ZKL and NY. Obtained funding: ZKL and NY. Technical or material support: WZ, ZKL and NY. Study supervision: ZKL and NY.

Corresponding authors

Correspondence to Nan Yang or Zhikui Liu.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments in our study were carried out in accordance with the Helsinki Declaration, and approved by the Ethics Committee the First Affiliated Hospital of Xi’an Jiaotong University (XJTU-2021-668). Patients were informed that the resected specimens were stored by the hospital and potentially used for scientific research, and that their privacy would be maintained. All patients provided informed consent prior to undergoing screening procedures. Our study protocol was approved by the Ethics Committee of Xi’an Jiaotong University (Xi’an, China).

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Zhao, W., Mo, H., Liu, R. et al. Matrix stiffness-induced upregulation of histone acetyltransferase KAT6A promotes hepatocellular carcinoma progression through regulating SOX2 expression. Br J Cancer 127, 202–210 (2022). https://doi.org/10.1038/s41416-022-01784-9

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