Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex

Abstract

Key Points• The SALL4/NuRD/PTEN pathway is important for acute myeloid leukemogenesis.• Targeting AML can be achieved by blocking the interaction between transcription factor SALL4 and the epigenetic NuRD complex.An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. IntroductionMembers of the SAL gene family belong to a group of C2H2 zinc finger transcription factors characterized by multiple zinc finger domains present in the protein. 1,2 Sal is a nonclustered regionspecific homeobox gene that plays an essential role in Drosophila, and Sal-related genes have been isolated from Caenorhabditis elegans, 3 fish, 4 frogs (Xenopus), 5,6 mice, 7 and humans. 2 Each of these homologs is expressed during embryonic development and in a more limited set of specific adult tissues. Murine Sall4 also plays a crucial role in development. Sall4-null mice die at embryonic day 6.5. [8][9][10][11] We have shown that murine Sall4 is essential for the maintenance of pluripotency and self-renewal properties of embryonic stem cells by interacting with 2 other key regulators, Nanog and Oct4. 11,12 After birth, SALL4 expression is down-regulated and absent in most adult tissues. However, SALL4 is expressed in various cancers, including a subset (30%) of solid tumors such as breast cancer, 13 ovarian cancer, 14 gastric cancer, 15 Wilms tumor, 16 and germ cell tumors, 14,[17][18][19][20][21] as well as in leukemias-most notably, almost all cases of human acute myeloid leukemia (AML) 22 and approximately 75% of B-cell acute lymphoblastic lymphoma/ leukemia. 23 We have also reported that SALL4 is enriched in the "side-population" of the leukemia and solid tumor cells. This side population is implicated in drug resistance and cancer initiation and is used to isolate cancer initiation cells. 24 SALL4 expression is also correlated with worse prognosis in AML patients. 24 We have also s...

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

“…Consistently, HDAC inhibitors might be useful for the eradication of SALL4-positive HCC cells through their inhibitory effects on histone deacetylation by NuRD [39]. Encouragingly, a recent study demonstrated the utility of a SALL4-binding peptide to inhibit its binding to phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through interaction with HDAC, thereby targeting leukemia cells [21]. Further studies are required to understand the relationship between SALL4, the NuRD complex, and the maintenance of stemness in HCC.…”

“…However, it is difficult to directly target SALL4 as no studies have investigated the inhibition of its transcription using chemical or other approaches [21]. We therefore re-investigated the interaction networks associated with SALL4, and found that SALL4 activation appeared to induce epigenetic modification (Fig.…”

SALL4: An emerging cancer biomarker and target

“…Furthermore, interfering with the interaction of SALL4 and its epigenetic partner complex has therapeutic effects in cancer. Gao and colleagues have developed a peptide inhibitor that can compete with SALL4 in interacting with the HDAC complex [65]. They demonstrate that treating SALL4-expressing leukemic cells with this peptide leads to cell death through the reactivation of PTEN.…”

Oncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma

“…20 We tested whether this 12-AA SALL4 peptide was effective in targeting the SALL4-PTEN-AKT pathway and resulted in decreased viability of hepatocellular carcinoma cells. When 5 µM or 20 µM of nonmutant SALL4 peptide was added to SNU-398 cells, the number of viable cells was reduced, as compared with SNU-398 cells treated with control mutant peptide and scrambled peptide.…”