Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling

Abstract

The Hedgehog (Hh)/Gli signaling pathway controls cell proliferation and differentiation, is critical for the development of nearly every tissue and organ in vertebrates and is also involved in tumorigenesis. In this study, we characterize the oncoprotein SET/I2PP2A as a novel regulator of Hh signaling. Our previous work has shown that the zebrafish homologs of SET are expressed during early development and localized in the ciliated organs. In the present work, we show that CRISPR/Cas9-mediated knockdown of setb gene in zebrafish embryos resulted in cyclopia, a characteristic patterning defect previously reported in Hh mutants. Consistent with these findings, targeting setb gene using CRISPR/Cas9 or a setb morpholino, reduced Gli1-dependent mCherry expression in the Hedgehog reporter zebrafish line Tg(12xGliBS:mCherry-NLS). Likewise, SET loss of function by means of pharmacological inhibition and gene knockdown prevented the increase of Gli1 expression in mammalian cells in vitro. Conversely, overexpression of SET resulted in an increase of the expression of a Gli-dependent luciferase reporter, an effect likely attributable to the relief of the Sufu-mediated inhibition of Gli1. Collectively, our data support the involvement of SET in Gli1-mediated transcription and suggest the oncoprotein SET/I2PP2A as a new modulator of Hedgehog signaling.

PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ

“…In addition, we have recently reported the ability of C c to modulate PP2A activity by interacting with another PP2A inhibitor, namely ANP32B [49] . A potential role for C c regulating tumor progression by inducing PP2A release from its inhibitors SET/TAF-Iβ or ANP32B cannot be discarded, as disruption of PP2A inhibition by targeting SET/TAF-Iβ hinders the progression of certain kinds of tumors [38] , [85] , [86] . In this context, it is tempting to propose a plausible function for SET/TAF-Iβ and/or ANP32B in INTAC-mediated transcription, as well as a clear impact of nuclear C c over INTAC activity and its consequences in tumor development.…”