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.
Highlights
Primary liver cancer is the second leading cause of all cancer-related mortality [1]
Ectopic overexpression of Metastasis-associated 1 (MTA1) significantly decreased the phosphorylation of H1.2T146 (H1.2T146ph) without affecting total H1.2 expression in both the normal (Figures 1A,B) and hepatocellular carcinoma (HCC) cell lines (Figures 1C,D)
These results indicated that MTA1 directly or indirectly is inhibiting phosphorylation of H1.2
Summary
Primary liver cancer is the second leading cause of all cancer-related mortality [1]. In 2018, there were more than 800,000 newly diagnosed primary liver cancer cases and 750,000 deaths worldwide [1]. Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and occupies ∼80% of primary liver cancer [1]. MTA1 Downregulates H1.2T146 Phosphorylation in HCC [2, 3]. The molecular mechanism underlying the malignant and aggressive features of this tumor type remains largely undefined. Metastasis-associated 1 (MTA1) is overexpressed in several different types of human tumors, including liver cancer [4, 5]. Elevated MTA1 expression level positively correlates with poor prognosis of patients [6]. Expression of MTA1 is critical for metastatic progression [7,8,9], transcriptional regulation, and chromatin remodeling [10]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call