OVOL2 antagonizes TGF-β signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis

Abstract

Great progress has been achieved in the study of the role of TGF-β signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-β signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-β signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-β signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-β signaling output level in vitro and in vivo. The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression.

OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma

“…The dysregulation of EMT-related TFs has been implicated in cancer progression. The role of OVOL2, an EMT-repressing TF, in suppressing metastasis has been shown in several human cancers, such as breast cancer, colorectal cancer and lung cancer 26 , 27 , 29 , 30 , 36 . In this report, by studying subclonal populations derived from the typical NPC cell line CNE2 that display relatively stable and contrasting phenotypes (S26: epithelial; S18: mesenchymal), we found that OVOL2 was the most significantly changed EMT-TF between the two subclones ( Figure 1 ), and functional analysis suggested that OVOL2 acts not only as a suppressor of metastasis (Figure 3 ) but also as a potent tumor suppressor ( Figure 4 ).…”

“…OVOL2 is an evolutionarily conserved protein that is involved in many important physiological processes, such as oogenesis in drosophila and mice 20 , 21 , cranial neural tube development 22 , mammary morphogenesis 23 , angiogenesis, heart formation and placental development 24 in mice, and ectoderm differentiation in human cells 25 through EMT regulation. Down-regulation of OVOL2 has been found in a variety of cancers, and OVOL2 was reported to inhibit EMT and metastasis by suppressing ZEB1 in breast cancer 26 , TWIST in lung cancer 27 , c-Myc in cutaneous squamous cell carcinoma 28 , Wnt signaling in colorectal cancer 29 and TGF-β signaling in breast cancer 30 .…”

Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

“…R-SMADs (SMAD2 and 3) bind to the Co-SMAD, SMAD4, to form complexes that modulate downstream gene expression in the nucleus (33). Previous studies have uncovered a connection between canonical SMAD4 signaling and EMT (34,35). Therefore, it is necessary to test the role of SMAD4 in EMT in renal carcinoma.…”

Shavenbaby and Yorkie mediate Hippo signaling to protect adult stem cells from apoptosis

“…The activity of OvoL might help stabilizing a hybrid E/M phenotype 21, 25 , providing many advantages for both tumors and normal stem cells 28 . Indeed, recent data show that, like adult somatic stem cells, the most aggressive tumors often display a hybrid phenotype between mesenchymal and epithelial states 27 , and the expression of specific OvoL isoforms can annihilate the metastatic potential of mammary tumors 29,19 . In addition, OvoL/Svb factors have been linked to the control of various progenitors/stem cells, from basal invertebrates 30 to mammals 31–33 .…”