Sox4 functions as a positive regulator of β-catenin signaling through upregulation of TCF4 during morular differentiation of endometrial carcinomas

Abstract

Sox factors function as either activators or repressors of b-catenin/TCF transcription depending on the cellular context and associated interacting proteins. Our previous study provided evidence that alteration in b-catenin signaling is an essential event during transdifferentiation toward the morular phenotype of endometrial carcinomas (Em Cas). Here, we focused on related functional roles of Sox factors. Of eight Sox factors investigated, Sox4 could enhance b-catenin/TCF4 transcription, through upregulation of TCF4 at the transcription level, without any direct b-catenin association. Cells stably overexpressing Sox4 showed significant decreases in proliferation rate, along with increases in expression of p21 WAF1 , as well as TCF4, in contrast to increased cell growth observed with knockdown. Of these factors, only Sox7 could transcriptionally upregulate Sox4 expression, but it also resulted in not only inhibition of Sox4-meditated activation of b-catenin/TCF4-driven transcription, but also repression of its own promoter activity, indicating the existence of very complex feedback loop for Sox-mediated signal cascades. Finally, Sox4 immunoreactivity was frequently pronounced in morular lesions of Em Cas, the expression being positively correlated with status of b-catenin, TCF4, and Sox7, and inversely with cell proliferation. These data therefore suggest that Sox4 may serve as a positive regulator of b-catenin signaling through alteration in TCF4 expression during morular differentiation of Em Ca cells, leading to inhibition of cell proliferation. In addition, Sox7 may also participate in the process, having complex roles in modulation of signaling.

SOX4 is overexpressed in diffusely infiltrating astrocytoma and confers poor prognosis

“…Ectopic SOX4 expression may induce EMT and confer metastatic properties in vitro such as increased migration and enhanced stem cell properties . SOX4 may also positively regulate the β‐catenin signaling pathway by upregulating transcription factor 4 (TCF4) in endometrial cancer …”

“…In addition to the regulation by TGF‐β‐Smad2/3 signalling described above, SOX4 has been shown to be transcriptionally regulated by SOX7 in endometrial cancer cells. Transfection of SOX7 resulted in activation of the SOX4 promoter by about 6.5‐fold, leading to increased SOX4 expression at both mRNA and protein levels . Gene amplification may also lead to SOX4 overexpression.…”

The regulation of β-catenin activity and function in cancer: therapeutic opportunities

“…A lower HOXB13 expression in colorectal cancer confers TCF4-mediated transactivation [76]. On the contrary, SOX4 activates β-catenin/TCF4 transcription by upregulating TCF4 at the transcriptional level without a direct β-catenin association [77]. As a tumor suppressor, RUNX3 inactivation occurs in many cancer types, especially in more than 80% of gastric cancers.…”

Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with β-catenin/p300 complexes in endometrial carcinoma cells

“…A similar finding was also observed in a case of Sox7, which may be important for changes in cell kinetics from proliferative to secretory stages in the normal endometrium. 44 Interestingly, HIF-1a protein has been shown to be upregulated under normoxic condition in response to growth factors, hormones, coagulation factors, cytokines, and vasoactive peptide, [45][46][47][48] allowing us to speculate that other factors, in particular estrogen, may serve as positive regulators for HIF-1a expression during the menstrual cycle, independent of O 2 tension. In contrast, the relatively higher HIF-1a expression in both glandular and stromal components in menstrual stages may be simply due to hypoxic effects.…”