HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity

Abstract

a b s t r a c tHepatocellular carcinoma (HCC) is the most common type of liver cancer. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation, cell cycle progression and developmental events. However, its biological roles in the development of HCC remain largely unexplored. In the present study, we found that mRNA and protein levels of HDAC6 were up-regulated in HCC tissues and cell lines. The proinflammatory cytokines, which were up-regulated in the human HCC microenvironment, increased HDAC6 expression through a proximal NF-kappaB binding site on the HDAC6 gene promoter. Furthermore, overexpression of HDAC6 could promote cell proliferation in HCC cell lines. In contrast, HDAC6 knockdown using small interfering RNA inhibited cell proliferation. At the molecular level, we demonstrated that HDAC6 could interact with p53 and attenuate its transcriptional activity through promotion of its degradation. Therefore, our results suggest a previously unknown HDAC6-p53 molecular network controlling HCC development.

A Decrease of Histone Deacetylase 6 Expression Caused by Helicobacter Pylori Infection is Associated with Oncogenic Transformation in Gastric Cancer

“…Furthermore, clinical data showed that the level of HDAC6 in HCC was significantly lower than that in hepatitis and liver fibrosis. Opposite results have also been reported in HCC patients [19]. Upregulated HDAC6 were detected in HCC tissues and cell lines at the mRNA and protein levels.…”

“…HDAC6 was shown to play an important role in cell proliferation through the NF-κB signaling pathway. Activation of NF-κB leads to the overexpression of HDAC6 at the transcriptional level since the promoter of HDAC6 contains a binding site of NF-κB [19]. Thus, the role of HDAC6 in the development of HCC is controversial, and the association of HDAC6 expression with GC is also unclear.…”

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…HDAC6 is particularly well suited for specific inhibition by being notably different from other HDACs with regard to protein structure, cellular localization, and its substrates, while still being involved in the regulation of cellular process like proliferation, migration, invasion and especially cellular stress response. 10,26,27 Moreover, HDAC6 has been reported to be overexpressed in a number of different cancer types such as ovarian, gastric, and breast cancer, oral squamous carcinoma and acute myeloid leukemia. 11,[28][29][30][31] In bladder cancer, HDAC6 expression and function has scarcely been investigated.…”

“…Similarly variable results on HDAC6 expression levels have been published for hepatocellular cancers. 27,37,38 Furthermore, HDAC6 has been reported to stimulate proliferation in the latter tumor type. In breast cancer, HDAC6 expression was likewise variable 29 and particularly strong in small tumors with low histological grade.…”

Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma

“…16,22,23 HDAC6 has also been studied in cancers because of its to ability to orchestrate a variety of cellular processes that are crucial for cancer pathogenesis. 24 Overexpression of HDAC6 has been demonstrated in hepatocellular carcinomas, 25 CTCL, 17 ALL, 22 and breast cancers. 26,27 Moreover, in contrast to increased Class I HDAC expression, which for the most part is an indicator of inferior survival, overexpression of HDAC6 has been largely associated with both improved overall (OS) and progression-free survival (PFS), including in studies of CTCL, 17 breast cancer, 26,27 lung cancer, 28 DLBCL, 20 and CLL.…”