Coexpression of SALL4 with HDAC1 and/or HDAC2 is associated with underexpression of PTEN and poor prognosis in patients with hepatocellular carcinoma

Abstract

Spalt-like transcriptional factor 4 (SALL4), a stem marker, is reactivated in several cancers. A previous study has demonstrated that SALL4 interacts with the nucleosome remodeling deacetylase complex, which contains histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2). In this study, we investigated the expression status of SALL4, HDAC1, and HDAC2 and their relationship with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by immunohistochemical analysis of the posthepatectomy specimens of 135 patients with hepatocellular carcinoma who were treated at our hospital. Ninety-two frozen samples were subjected to quantitative reverse-transcription polymerase chain reaction analysis to detect the messenger RNA levels of PTEN. Seventy-six (56%) of 135 patients were positive for SALL4, and this group had a higher prevalence of hepatitis B antigen, a higher value of α-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKAII) and poor histologic differentiation. The 5-year survival rate was significantly lower in the SALL4-positive group. High HDAC1 expression (51%) was correlated with a poor histologic differentiation and a poor prognosis. High HDAC2 expression (46%) was associated with a higher prevalence of hepatitis B antigen positivity, a poor histologic differentiation and higher prevalence of vascular invasion, and a lower 5-year survival rate. Coexpression of SALL4 with HDAC1 and/or HDAC2 was correlated with underexpression of PTEN. Moreover, multivariable analysis revealed that coexpression of SALL4 with HDAC1 and/or HDAC2 was predictive of an unfavorable prognosis. Our data thus suggested that the combination of SALL4, HDAC1, and HDAC2 may provide a potential target for molecular therapy.

Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist

“…Some investigators reported that SALL4 was useful to distinguish hepatoid adenocarcinomas from hepatocellular carcinomas because no hepatocellular carcinomas showed positive expressions of SALL4 [12,50]. However, others reported hepatocellular carcinomas occasionally showed positive expressions of SALL4 [51,52]. Therefore, diagnosis of hepatoid adenocarcinomas is still challenging especially in cases of hepatic metastasis, and it merits further investigations.…”

Clinical significance of HDAC1, -2 and -3 expression levels in esophageal squamous cell carcinoma

“…There is a significant association between HDAC1 high expression and advanced age (26). High levels of HDAC1 expression are associated with a poor histological differentiation and prognosis in liver cell carcinoma (27). There is higher expression of HDAC1 in gastrointestinal malignant tumor, particularly in colorectal cancer and HDAC1 expression is closely related to clinical characteristics of gastrointestinal cancer (8).…”

Regulations of Tumor Suppressor Gene PTEN and Its Potential as Therapeutic Target

“…Methylation status of the 5' CpG islands of PTEN is closely associated with the silencing of PTEN in gastric carcinoma, gallbladder cancer and breast cancer [8][9][10], but Ten-Eleven Translocation 1 (TET1) inhibits gastric cancer growth and metastasis by demethylating PTEN promoter and inducing its re-expression [11]. Transcription factor SALL4 represses PTEN expression by recruiting histone deacetylase HDAC1 and HDAC2, and clinically, it is associated with downregulation of PTEN and tumor prognosis in hepatocellular carcinoma [12]. Other transcription factors c-Jun and polycomb group protein Bmi-1 were also reported to negatively regulate PTEN transcription [13,14].…”