Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion.

ABSTRACT: Transforming growth factor β (TGFβ) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFβ-targeted therapies. The major TGFβ downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFβ. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFβ signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SAR

SUBMITTER: Brochu-Gaudreau K 

PROVIDER: S-EPMC9179584 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature