Acetylated Kruppel-like factor 5 (KLF5) is essential for transforming growth factor-β (TGF-β) to properly regulate gene transcription in the inhibition of cell proliferation and tumor growth. Ras oncogenic signaling can convert TGF-β from a tumor suppressor to a tumor promoter; however, its ability to utilize the KLF5 transcription factor to modulate TGF-β functions is still unknown. Therefore, in this study, we sought to determine whether Ras signaling altered TGF-β-induced KLF5 acetylation and the assembly of the p300-KLF5-SMADs transcriptional complex in gene regulation. Not only did we determine that Ras signaling inhibited TGF-β-induced KLF5 acetylation and interfered with TGF-β function in p15 induction and Myc repression, but also TGF-β-induced SMAD3 C-terminal region phosphorylation was necessary for TGF-β to induce KLF5 acetylation. Moreover, Ras activation further interrupted the interactions amongst p300, KLF5, and SMAD4, as well as the binding of p300-KLF5-SMADs complex onto the TGF-β-responsive promoter elements for both p15 and Myc. These findings suggested that KLF5 mediated the crosstalk between TGF-β and Ras signaling, and that suppression of TGF-β-induced KLF5 acetylation by Ras activation; this altered TGF-β-induced assembly of p300-KLF5-SMADs complex onto gene promoters to convert the function of TGF-β in gene regulation.
Keywords: KLF5; Myc; Ras; SMAD3; TGF-β; p15.
© 2019 Wiley Periodicals, Inc.