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  • MTA1 Promotes Hepatocellular Carcinoma Progression by Downregulation of DNA-PK-Mediated H1.2T146 Phosphorylation.

MTA1 Promotes Hepatocellular Carcinoma Progression by Downregulation of DNA-PK-Mediated H1.2T146 Phosphorylation.

Frontiers in oncology (2020-05-22)
Yu-Hui Li, Ming Zhong, Hong-Liang Zang, Xiao-Feng Tian
ABSTRACT

Global incidence and mortality associated with hepatocellular carcinoma (HCC) is steadily increasing. Metastasis-associated 1 (MTA1) can induce tumorigenesis and metastatic progression in HCC. However, the mechanistic details of MTA1-mediated regulation of HCC has not been completely defined. Epigenetic histone modification is closely related to tumor development. Histone cluster 1 H1 family member c (H1.2) is important for epigenetic histone modification and chromatin remodeling; however, whether it has a role in HCC tumorigenesis is not known. In the current study, we confirmed that MTA1 promoted HCC cell growth and migration. Our results further show that MTA1 inhibited the phosphorylation of histone cluster 1 H1 family member c (H1.2) at threonine-146 residue (T146) (H1.2T146ph). MTA1 inhibited H1.2T146ph by mediating proteasomal degradation of the DNA protein kinase (DNA-PK). Pharmacological inhibition of proteasomal degradation of DNA-PK or genetic ablation of E3 ligase mouse double minute 2 (MDM2) rescued expression of DNA-PK, and subsequent phosphorylation of H1.2. MTA1's role in HCC was inhibited by ectopic expression of H1.2T146ph in HCC cell lines. Our results showed that H1.2T146ph can bind to MTA1 target genes. Collectively, our study confirms that MTA1 functions as an oncogene and promotes HCC progression. The epigenetic histone modifier H1.2T146ph exerts critical role in the regulation of MTA1-induced tumorigenesis. MTA1 regulates posttranslational activation of H1.2 by regulating the cognate kinase, DNA-PK, via the ubiquitin proteasome system. MTA1 expression was inversely correlated to both DNA-PK and phosphorylated H1.2 in HCC tissue specimens compared to tumor adjacent normal hepatic tissue, revealing that the MTA1/MDM2/DNA-PK/H1.2 is an important therapeutic axis in HCC.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
SDS Lysis Buffer - for use in ChIP Assay, For use in Chromatin Immunoprecipitation assays.
Sigma-Aldrich
TE Buffer - for use in ChIP Assays, For use in Chromatin Immunoprecipitation assays.
Sigma-Aldrich
Anti-MDM2 antibody ,Mouse monoclonal, clone HDM2-323, purified from hybridoma cell culture
Sigma-Aldrich
High Salt Immune Complex Wash Buffer, For use in the Chromatin Immunoprecipitation Assay Kits.
Sigma-Aldrich
Low Salt Immune Complex Wash Buffer, For use in the Chromatin Immunoprecipitation Assay Kits.
Sigma-Aldrich
LiCl Immune Complex Wash Buffer, For use in Chromatin Immunoprecipitation assays.
Sigma-Aldrich
Chromatin Immunoprecipitation (ChIP) Dilution Buffer, For use in the Chromatin Immunoprecipitation Assays.
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)