2. Academic Validation
  3. Matrix stiffness-induced YEATS2 drives HCC progression via epigenetic activation of the TGFBR2-TAZ-AKT pathway

Matrix stiffness-induced YEATS2 drives HCC progression via epigenetic activation of the TGFBR2-TAZ-AKT pathway

  • Cell Death Differ. 2026 Mar 3. doi: 10.1038/s41418-026-01697-7.
Yueqin Zhang # 1,  Lidong Cao # 1,  Xiao Wang # 1,  Lu Zhou 1,  Weiyi Zhao 1,  Mu He 1 2,  Jun Tong 1 2,  Qingqing Wu 1 2,  Muhammad Umar 3,  Junjie Qian 1,  Xiaobin Fei 1,  Jie Liu 1,  Mengmeng Dong 4,  Chengwu Zhang 5,  Changwei Dou 6
Affiliations

Affiliations

  • 1 General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Graduate School of Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 3 International Education College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
  • 4 Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 5 General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 6 General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41776086 DOI: 10.1038/s41418-026-01697-7
Abstract

YEATS2, a crucial component of Histone Acetyltransferase (HAT) complexes, has been identified as overexpressed in multiple human cancers and is correlated with tumor advancement and unfavorable clinical outcomes. The precise role of YEATS2 in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study seeks to investigate the function and mechanisms by which YEATS2 facilitates HCC growth and metastasis. Our results demonstrate that YEATS2 expression is markedly elevated in HCC tissues and is correlated with unfavorable clinical characteristics and decreased survival rates. Functional assays conducted both in vitro and in vivo reveal that YEATS2 enhances HCC cell proliferation, migration, and invasion. Through RNA Sequencing and mass spectrometry analyses, this study revealed YEATS2 activates the TAZ/Akt signaling pathway and promotes aerobic glycolysis via the upregulation of TGFBR2. Chromatin immunoprecipitation and co-immunoprecipitation assays further confirm that YEATS2 interacts with KAT2A, leading to increased levels of H3K9ac and H3K14ac within the promoter region of TGFBR2, thereby promoting its transcriptional activation. Moreover, increased matrix stiffness was found to induce YEATS2 expression through augmenting the binding of HIF-1α to the YEATS2 promoter. Collectively, these results delineate a novel YEATS2-TGFBR2-TAZ-AKT signaling axis that connects matrix stiffness to metabolic reprogramming and HCC progression, highlighting YEATS2 as a potential therapeutic target for HCC.

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