The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma

Abstract

Background & Aims: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subtypes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features. Methods: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined. Results: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells. Conclusions: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features. Ó

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

“…We recently demonstrated that HDACs are activated in EpCAM + HCCs, and that HDAC inhibitors successfully inhibit the growth of EpCAM + HCC cell lines [18]. We evaluated the expression of HDAC1 in 38 surgically resected snap-frozen specimens using qRT-PCR.…”

“…It has been reported by three independent groups that SALL4 is a biomarker of HCCs with stem-like gene expression signatures and a poor prognosis [18,25,26]. SALL4 was recently found to directly interact with the epigenetic modulator nucleosome remodeling and histone deacetylase (NuRD) complex [27], thereby altering the histone modifications associated with stemness.…”

“…SALL4 was recently found to directly interact with the epigenetic modulator nucleosome remodeling and histone deacetylase (NuRD) complex [27], thereby altering the histone modifications associated with stemness. Indeed, we have demonstrated that SALL4-positive HCCs have high histone deacetylase (HDAC) activity and are chemosensitive to HDAC inhibitors which reduce SALL4 expression [18].…”

Hierarchical potential differentiation of liver cancer stem cells

“…39 Others regard SALL4 to be a marker of liver CSCs, which can be used to predict HCC treatment outcomes. [40][41][42] Furthermore, expression of phosphatase and tensin homologue protein was suppressed and the formation of tumors in xenograft models was inhibited by overexpression of SALL4. 43 Thus, inhibiting expression of SALL4 can inhibit proliferation and differentiation of liver cancer cells.…”

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

“…Zebularine, a DNA methyltransferase (DNMT) inhibitor, declined CSC properties such as self-renewal and tumor-initiating capacities in HCC cells [43]. Histone deacetylase (HDAC) inhibitors such as trichostatin A and vorinostat have been shown to preferentially suppress the cell growth of SALL4-overexpressing HCC cell lines compared with that of SALL4 − HCC cell lines [44,45]. These indings suggest that epigenetic therapy using DNMT inhibitors and/ or HDAC inhibitors may be a promising approach for the eradication of CSCs in HCC.…”