Abstract
BackgroundCancer stem cells (CSCs) are the root of human cancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study.ResultsOverexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer.ConclusionsThe results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1 is a potential drug target for eradicating SOX4-driven human CSCs.
Highlights
Cancer is a highly heterogeneous malignant disease that consists of at least two types of subpopulations: a small number of self-renewing cancer stem cells (CSCs), named tumor-initiating cells (TICs), and a majority of SOX (SRY-related HMG-box) family proteins are a group of evolutionarily conserved transcription factors containing at least 20 members grouped into eight classes (SoxA to SoxH) that present a highly conserved high-mobility group (HMG) domain and playLiu et al Cell Biosci (2021) 11:23 fundamental physiological and pathological roles, such as cell fate decision, testis determination, male fertility as well as normal organ and cancer development [4,5,6]
By identification of SOX4-induced proteome changes in colorectal cancer stem cells (CRC-SCs), we investigated the potential molecular effects of SOX4 in cancer cell (CRC)-SCs and found that SOX4 transcriptionally regulates HDAC1 to support the stemness of Cancer stem cells (CSCs)
To further confirm the critical role of HDAC1 in SOX4 supporting CRC stemness, we investigated the relationship between HDAC1 and CRC-SCs, and examined whether overexpression of HDAC1 in CRC cells could produce a similar effect with SOX4 overexpression
Summary
Cancer is a highly heterogeneous malignant disease that consists of at least two types of subpopulations: a small number of self-renewing cancer stem cells (CSCs), named tumor-initiating cells (TICs), and a majority of SOX (SRY-related HMG-box) family proteins are a group of evolutionarily conserved transcription factors containing at least 20 members grouped into eight classes (SoxA to SoxH) that present a highly conserved high-mobility group (HMG) domain and playLiu et al Cell Biosci (2021) 11:23 fundamental physiological and pathological roles, such as cell fate decision, testis determination, male fertility as well as normal organ and cancer development [4,5,6]. Cancer is a highly heterogeneous malignant disease that consists of at least two types of subpopulations: a small number of self-renewing cancer stem cells (CSCs), named tumor-initiating cells (TICs), and a majority of SOX (SRY-related HMG-box) family proteins are a group of evolutionarily conserved transcription factors containing at least 20 members grouped into eight classes (SoxA to SoxH) that present a highly conserved high-mobility group (HMG) domain and play. Despite the importance of SOX4 in cancer development, its role in stemness maintenance of human cancer has not been fully understood. Despite massive studies, the upstream regulation of HDAC1 and its role in cancer stemness remain elusive. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study
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