Abstract
Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.
Highlights
Colorectal cancer remains high incidence and mortality in recent years worldwide[1,2,3]
The mRNA and protein expressions of colorectal cancer stem cells (CSCs) markers, including CD133, CD44, Nanog, and Oct-4, were significantly induced compared to the parental cells maintained in serum-sustained medium (SSM) (Fig. 1C, D)
These results suggested the characteristics of CSCs in HCT116 and SW480 sphere-forming cells cultured in serum-free medium (SFM)
Summary
Colorectal cancer remains high incidence and mortality in recent years worldwide[1,2,3]. Despite the advances in early diagnostics and interventions, colorectal cancer frequently recurs and leads to heavy burden and death[4]. Studies have validated the crucial roles of cancer stem cells (CSCs) in the initiation, invasion, metastasis, and drug resistance in cancer progression[5]. Specific markers and several signal pathways have been found to participate in the development and maintenance of colorectal CSCs6. The protein p63, including multiple protein isoforms, are important transcription factors belong to the p53 family. According to the transcription start sites, the p63 gene translates to the trans-activating (TA) isoforms that contain an N-terminal exon encoding a p53-like transactivation domain and ΔN isoforms without this domain
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