Heat-shock cognate protein 70 (Hsc70), a molecular chaperone, is involved in multiple cellular functions. We previously demonstrated that Hsc70 is required for TGF-beta-induced Smad signaling in mesenchymal-like NRK-49F cells. In the present study, to compare the Hsc70 functions in TGF-beta-related signaling between epithelial and mesenchymal cells, we examined the effect of Hsc70 downregulation on TGF-beta-induced signaling in epithelial-like NRK-52E cells. TGF-beta-induced Smad signaling was suppressed in cells treated with small interfering RNA (siRNA) for Hsc70. Interestingly, despite interference with TGF-beta signaling, TGF-b-induced suppression of E-cadherin expression was not affected by Hsc70 knockdown. Instead, Hsc70 knockdown itself caused the suppression of E-cadherin expression at the transcription level in cells treated with Hsc70 siRNA. We also examined the effects of Hsc70 knockdown on the level of E-cadherin-gene repressors, such as Snail1, Slug, Zeb1, Zeb2, and Twist1, and found that transcription of the repressors was upregulated after 24- or 36-h treatment with Hsc70 siRNA. Collectively, these results indicate that, in addition to a supportive role in TGF-beta-induced signaling, Hsc70 supports E-cadherin expression through downregulation of the E-cadherin-gene repressors in NRK-52E cells, suggesting that Hsc70 plays a functional role to maintain the epithelial cell phenotype. (C) 2020 Elsevier Inc. All rights reserved.