Abstract
Altered transforming growth factor-β (TGF-β) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-β1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-β1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.
Highlights
Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression
Previous reports have demonstrated that TGF-b signalling and the subsequent biological events such as the epithelial-tomesenchymal transition (EMT) and angiogenesis are involved in the growth, invasion and metastasis of cancers[2,3,4,5,6,7]
We show that profilin-2 suppresses the nuclear localization of histone deacetylase 1 (HDAC1) by interacting with HDAC1, which epigenetically activates the transcription of Smad[2] and Smad[3] and thereby promotes human lung cancer growth and metastasis
Summary
Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression. Transforming growth factor-b (TGF-b) is a signal molecule with multiple cellular functions It plays important roles in regulating embryogenesis, tissue homeostasis and various pathophysiological events. We investigated the roles of profilin-2 in human lung cancer progression and its link with the TGF-b/Smad signalling. We show that profilin-2 suppresses the nuclear localization of histone deacetylase 1 (HDAC1) by interacting with HDAC1, which epigenetically activates the transcription of Smad[2] and Smad[3] and thereby promotes human lung cancer growth and metastasis. Our study provides an insight into how TGF-b/Smad signalling is regulated in lung cancers, and suggests a new molecular target for drug development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
