Abstract
Background
Dysregulation of histone deacetylases has been linked to diverse cancers. HDAC5 is a histone deacetylase belonging to Class IIa family of histone deacetylases. Limited substrate repertoire restricts the understanding of molecular mechanisms underlying its role in tumorigenesis.
Methods
We employed a biochemical screen to identify SATB1 as HDAC5-interacting protein. Coimmunoprecipitation and deacetylation assay were performed to validate SATB1 as a HDAC5 substrate. Proliferation, migration assay and xenograft studies were performed to determine the effect of HDAC5-SATB1 interaction on tumorigenesis.
Results
Here we report that HDAC5 binds to and deacetylates SATB1 at the conserved lysine 411 residue. Furthermore, dynamic regulation of acetylation at this site is determined by TIP60 acetyltransferase. We also established that HDAC5-mediated deacetylation is critical for SATB1-dependent downregulation of key tumor suppressor genes. Deacetylated SATB1 also represses SDHA-induced epigenetic remodeling and anti-proliferative transcriptional program. Thus, SATB1 spurs malignant phenotype in a HDAC5-dependent manner.
Conclusions
Our study highlights the pivotal role of HDAC5 in tumorigenesis. Our findings provide key insights into molecular mechanisms underlying SATB1 promoted tumor growth and metastasis.
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Acknowledgements
We thank the members of the Molecular Oncology Laboratory for helpful discussions. SS was supported by a fellowship from the Department of Biotechnology, Government of India. WT was supported by a fellowship from Department of Science & Technology, Government of India and RT was supported by a fellowship from Council of Scientific & Industrial Research (CSIR), Government of India. This work was supported by a grant from Science and Engineering Research Board, Government of India (CRG/2021/000603/IBS) to SD.
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SS and SD conceived the initial project. SS, WT, and SD conceptualised the study and designed the experiments. SS, WT, and SD developed the methodology. SS, WT and RT performed all the experiments. SS, WT, RT and SD analysed the data. SS, WT, and SD wrote the manuscript. All authors approved the final version of the article, including the authorship list.
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Sharma, S., Tyagi, W., Tamang, R. et al. HDAC5 modulates SATB1 transcriptional activity to promote lung adenocarcinoma. Br J Cancer 129, 586–600 (2023). https://doi.org/10.1038/s41416-023-02341-8
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DOI: https://doi.org/10.1038/s41416-023-02341-8