Abstract
SALL4, a member of the SALL family, is an embryonic stem cell regulator involved in self-renewal and pluripotency. Recently, SALL4 overexpression was found in malignant cancers, including lung cancer, hepatocellular carcinoma, breast cancer, gastric cancer, colorectal cancer, osteosarcoma, acute myeloid leukemia, ovarian cancer, and glioma. This review updates recent advances of our knowledge of the biology of SALL4 with a focus on its mechanisms and regulatory functions in tumors and human hematopoiesis. SALL4 overexpression promotes proliferation, development, invasion, and migration in cancers through activation of the Wnt/β-catenin, PI3K/AKT, and Notch signaling pathways; expression of mitochondrial oxidative phosphorylation genes; and inhibition of the expression of the Bcl-2 family, caspase-related proteins, and death receptors. Additionally, SALL4 regulates tumor progression correlated with the immune microenvironment involved in the TNF family and gene expression through epigenetic mechanisms, consequently affecting hematopoiesis. Therefore, SALL4 plays a critical oncogenic role in gene transcription and tumor growth. However, there are still some scientific hypotheses to be tested regarding whether SALL4 is a therapeutic target, such as different tumor microenvironments and drug resistance. Thus, an in-depth understanding and study of the functions and mechanisms of SALL4 in cancer may help develop novel strategies for cancer therapy.
Highlights
In the past 20 years, molecular targeted therapy and biological cellular immunotherapy have become popular therapeutic methods for tumors [1]
SALL4 overexpression in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells results in an increase in B-cell lymphoma 2 (Bcl-2) expression and cell survival [75], whereas SALL4 knockdown markedly inhibits Bcl-2 expression in prostate cancer [76], breast cancer [16,77], colorectal cancer (CRC) [78], and nasopharyngeal carcinoma (NPC) [79], and it induces the expression of pro-apoptotic Bax in prostate cancer [76] and NPC [79]
A previous study showed that SALL4 expression is abnormally high in lung cancer [130], indicating that a deep understanding of the function underlying the progression and prognosis of lung cancer involved in SALL4 is critical for promoting an early diagnosis and effective therapy
Summary
In the past 20 years, molecular targeted therapy and biological cellular immunotherapy have become popular therapeutic methods for tumors [1]. Recent studies have found the patterns of SALL4 to bind DNA-specific genes and regulate their expression, involved in ZFC, both in normal embryonic stem cells (ESCs) and SALL4-dependent tumors. The C-terminal ZFC of SALL4 is responsible for DNA binding, and SALL4 negatively regulates expression of a family of histone 3 lysine 9-specific demethylases (KDMs) in aggressive liver cancer cells [25]. SALL4 is a potential target for the diagnosis and treatment of cancer [18,30] It participates in the regulation of cell growth, cell cycle, and apoptosis via the expression of articulation-related genes, and it exerts biological effects as a transcription factor in the nucleus, where it plays a crucial role in the occurrence and development of various malignant tumors. Understanding the functions and mechanisms of SALL4 can provide novel insight into how SALL4 can be targeted in tumor therapies
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