Cooperatively transcriptional and epigenetic regulation of sonic hedgehog overexpression drives malignant potential of breast cancer

Abstract

Sonic hedgehog (Shh), a ligand of Hedgehog signaling pathway, is considered an important oncogene and an exciting potential therapeutic target in several cancers. Comprehensive understanding of the regulation mechanism of Shh in cancer cells is necessary to find an effective approach to selectively block its tumorigenic function. We and others previously demonstrated that nuclear factor-kappa B (NF-κB) activation and promoter hypomethylation contributed to the overexpression of Shh. However, the relationship between transcriptional and epigenetic regulation of Shh, and their roles in the malignant phenotype of cancer cells are still not clearly elucidated. In the present study, our data showed that the level of Shh was higher in breast cancer tissues with positive NF-κB nuclear staining and promoter hypomethylation. In addition, survival analysis revealed that Shh overexpression, but not hypomethylation and NF-κB nuclear staining, was a poor prognosis indicator for breast cancers. Moreover, in vitro data demonstrated that both NF-κB activation and hypomethylation in promoter region were positively associated with the overexpression of Shh. Mechanistically, the hypomethylation in Shh promoter could facilitate NF-κB binding to its site, and subsequently cooperate to induce transcription of Shh. Furthermore, the biological function data indicated that overexpressed Shh enhanced the self-renewal capacity and migration ability of breast cancer cells, which could be augmented by promoter demethylation and NF-κB activation. Overall, our findings reveal multiple and cooperative mechanisms of Shh upregulation in cancer cells, and the roles of Shh in tumor malignant behavior, thus suggesting a new strategy for therapeutic interventions to reduce Shh in tumors and improve patients’ prognosis.

Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

“…Moreover, overexpression of Shh was found in breast cancer tissues and survival analysis suggested that Shh overexpression was a poor prognosis indicator for breast cancers [8]. These evidence characterized that Shh overexpression was a critical event in breast carcinogenesis [8,9]. In addition, Shh activation induced transcription of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) and caused a robust increase of glycolytic metabolism in medulloblastoma [10].…”

“…In human hepatocellular carcinoma (HCC), Shh signaling pathway mediates cancer cells invasion and metastasis by increasing MMP-9 expression via ERK pathway [7]. Moreover, overexpression of Shh was found in breast cancer tissues and survival analysis suggested that Shh overexpression was a poor prognosis indicator for breast cancers [8]. These evidence characterized that Shh overexpression was a critical event in breast carcinogenesis [8,9].…”

Acute Alcohol Intoxication Impairs Sonic Hedgehog‐Gli1 Signaling and Activation of Primitive Hematopoietic Precursor Cells in the Early Stage of Host Response to Bacteremia

“…These data suggest that impaired activation of ERK1/ 2 signaling may serve as a mechanism underlying the inhibited up-regulation of SHH expression by marrow hematopoietic cells during systemic E. coli infection in mice acutely intoxicated with alcohol. In addition to SP1, studies have shown that other transcription factors including NF-jB and STAT6 may participate in the regulation of SHH expression (Duan et al, 2015;Wang et al, 2020). During infection and inflammation, cytokines and other endogenous mediators can signal through these transcription factors.…”

Dihydroartemisinin Sensitizes Esophageal Squamous Cell Carcinoma to Cisplatin by Inhibiting Sonic Hedgehog Signaling

“…So the target genes of Glis were activated, including SOX2 [13] and PTCH1 [14]. It has been well demonstrated that the activation of Shh signaling was involved in the development and progression of many types of cancer [15][16][17][18], including ESCC [19,20]. Moreover, the critical roles of Shh pathway in maintaining cancer stem cells (CSCs) and drug resistance have also been well illustrated [13,21,22].…”