Dataset Information

OTUD4 enhances TGF? signalling through regulation of the TGF? receptor complex.

ABSTRACT: Systematic control of the transforming growth factor-? (TGF?) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGF? pathway that functions through a positive feedback loop to enhance overall TGF? activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGF? activity. Specifically, we find that OTUD4 enhances TGF? signalling by promoting the membrane presence of TGF? receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGF? negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGF? pathway to enhance TGF? activity.

SUBMITTER: Jaynes PW

PROVIDER: S-EPMC7519109 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex.

Jaynes Patrick William PW Iyengar Prasanna Vasudevan PV Lui Sarah Kit Leng SKL Tan Tuan Zea TZ Vasilevski Natali N Wright Sarah Christine Elizabeth SCE Verdile Giuseppe G Jeyasekharan Anand D AD Eichhorn Pieter Johan Adam PJA

Scientific reports 20200924 1

Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both cataly ...[more]

PMID: 32973272

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Project description:BackgroundEpigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer.MethodChromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs.ResultsH3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites.ConclusionOur results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.

Dataset Information

OTUD4 enhances TGF? signalling through regulation of the TGF? receptor complex.

Publications

OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex.

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