# SATB1

## Overview
SATB1 (Special AT-rich sequence-binding protein 1) is a gene that encodes the SATB homeobox 1 protein, a transcription factor known for its pivotal role in chromatin organization and gene regulation. The SATB1 protein is categorized as a chromatin organizer and transcriptional regulator, characterized by its ability to bind to specific DNA sequences known as matrix attachment regions (MARs). This binding facilitates the spatial arrangement of chromatin, thereby influencing gene expression. SATB1 is particularly significant in the development and differentiation of T cells and plays a crucial role in epidermal development by regulating chromatin remodeling and gene expression associated with differentiation. The protein's structure includes multiple domains, such as a ubiquitin-like domain, homeodomain, and CUT domains, which are essential for its DNA-binding and regulatory functions. SATB1's activity is modulated by post-translational modifications, including phosphorylation and acetylation, which affect its interactions with other proteins and its role in transcriptional regulation (Wang2014Crystal; Fessing2011p63; Purbey2008PDZ).

## Structure
SATB1 (SATB homeobox 1) is a multidomain protein that plays a crucial role in chromatin organization and gene regulation. The protein's structure includes several distinct domains that contribute to its function. The N-terminal module of SATB1 consists of a ubiquitin-like domain (ULD) and a CUT repeat-like (CUTL) domain, connected by a loop and a linker-helix. The ULD is composed of four antiparallel β-sheets flanked by four α-helices, resembling a ubiquitin domain (Wang2012The; Wang2014Crystal). This domain is essential for the protein's ability to form a tetramer, which is crucial for its DNA-binding activity (Wang2012The).

SATB1 also contains a homeodomain and two CUT domains, which are involved in DNA recognition and binding. The homeodomain is located at the C terminus and shares structural similarities with the engrailed class of homeodomains, featuring a unique substitution of the WFQ motif with FFQ in the third helix (Dickinson1997An). The CUT domains, particularly the CUT1 domain, are involved in binding to matrix attachment regions (MARs) of DNA, with the third helix entering the major groove of the DNA (Yamasaki2007Structural).

Post-translational modifications such as phosphorylation and acetylation can influence SATB1's activity, and the protein has several splice variant isoforms, which may differ in their functional roles. These structural features enable SATB1 to organize chromatin into loop domains, facilitating its role in regulating gene expression.

## Function
SATB1 (SATB homeobox 1) is a transcription factor that plays a crucial role in organizing chromatin structure and regulating gene expression in healthy human cells. It binds to specific genomic regions known as matrix attachment regions (MARs), influencing the spatial arrangement of chromatin and facilitating or repressing transcription. SATB1 is particularly important in the development and differentiation of T cells, where it is highly expressed in the cortex of the thymus, especially in CD4+ CD8+ thymocytes. Its expression decreases as thymocytes differentiate into single positive T cells, indicating its role in early T cell development (Agrelo2009SATB1).

In the context of epidermal development, SATB1 is regulated by the p63 transcription factor and is essential for chromatin remodeling during keratinocyte differentiation. It binds to the epidermal differentiation complex (EDC) locus, promoting the expression of differentiation-associated genes. SATB1 deficiency leads to decompression of the EDC locus and reduced expression of these genes, resulting in morphological changes in the epidermis (Fessing2011p63). SATB1 also influences cell proliferation in the developing epidermis, suggesting its broader role in cell cycle regulation (Fessing2011p63).

## Clinical Significance
SATB1 (SATB homeobox 1) is significantly implicated in various cancers, primarily through alterations in its expression levels rather than mutations. In breast cancer, SATB1 is overexpressed in metastatic and aggressive tumors, correlating with poor prognosis and shorter survival rates. Its knockdown in aggressive breast cancer cells can reverse their malignant phenotype, suggesting its potential as a therapeutic target (Mir2012Chromatin; Kohwi-Shigematsu2013Genome). SATB1 also plays a role in colorectal cancer, where its loss is associated with poor survival, particularly in right-sided colon cancers (Al‐Sohaily2014Loss). In pancreatic ductal adenocarcinoma, SATB1 overexpression is linked to gemcitabine resistance and poor prognosis (Wei2018Cancer-associated).

SATB1 influences tumor progression by regulating genes involved in metastasis and epithelial-mesenchymal transition (EMT), promoting aggressive cancer phenotypes (Frömberg2018The; GlatzelPlucińska2019The). It also affects tumor immunity by modulating regulatory T cells and influencing the expression of immune checkpoint proteins like PD-1 (Naik2018SATB). These roles underscore SATB1's potential as a prognostic marker and therapeutic target in cancer treatment.

## Interactions
SATB1 interacts with DNA through its PDZ domain-mediated dimerization and homeodomain (HD)-directed specificity. It binds DNA as a homodimer, with each monomer interacting in an antiparallel fashion. The PDZ domain is crucial for dimerization, enhancing DNA-binding affinity, while the C-terminal HD provides specificity by binding primarily through the minor groove. The central domain (CD) binds through the major groove with low specificity (Purbey2008PDZ).

SATB1 also interacts with various proteins, including CtBP1 and HDAC1, forming complexes that mediate transcriptional repression. Acetylation of SATB1 reduces its association with CtBP1, leading to derepression of target genes (Purbey2009Acetylation-Dependent). SATB1's interaction with PIAS1 is regulated by phosphorylation, which affects its subnuclear localization and stability. The LXXLL motif and phosphorylation at T188 are critical for PIAS1 binding (Tan2010Phosphorylation-Dependent).

In breast cancer cells, SATB1 interacts with F-actin, which is important for mechanisms of active cell death. This interaction is observed during geldanamycin-induced cell death, suggesting a role in nuclear degradation during apoptosis (Grzanka2015The).


## References


[1. (Wang2012The) Zheng Wang, Xue Yang, Xinlei Chu, Jinxiu Zhang, Hao Zhou, Yuequan Shen, and Jiafu Long. The structural basis for the oligomerization of the n-terminal domain of satb1. Nucleic Acids Research, 40(9):4193–4202, January 2012. URL: http://dx.doi.org/10.1093/nar/gkr1284, doi:10.1093/nar/gkr1284. This article has 47 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkr1284)

[2. (Dickinson1997An) Liliane A. Dickinson, Craig D. Dickinson, and Terumi Kohwi-Shigematsu. An atypical homeodomain in satb1 promotes specific recognition of the key structural element in a matrix attachment region. Journal of Biological Chemistry, 272(17):11463–11470, April 1997. URL: http://dx.doi.org/10.1074/jbc.272.17.11463, doi:10.1074/jbc.272.17.11463. This article has 95 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.272.17.11463)

[3. (Mir2012Chromatin) Rafeeq Mir, Saurabh J. Pradhan, and Sanjeev Galande. Chromatin organizer satb1 as a novel molecular target for cancer therapy. Current Drug Targets, 13(13):1603–1615, October 2012. URL: http://dx.doi.org/10.2174/138945012803530008, doi:10.2174/138945012803530008. This article has 47 citations and is from a peer-reviewed journal.](https://doi.org/10.2174/138945012803530008)

[4. (Grzanka2015The) Dariusz Grzanka, Anna E. Kowalczyk, Magdalena Izdebska, Anna Klimaszewska-Wisniewska, and Maciej Gagat. The interactions between satb1 and f-actin are important for mechanisms of active cell death. Folia Histochemica et Cytobiologica, 53(2):152–161, July 2015. URL: http://dx.doi.org/10.5603/fhc.a2015.0018, doi:10.5603/fhc.a2015.0018. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.5603/fhc.a2015.0018)

[5. (Purbey2009Acetylation-Dependent) Prabhat Kumar Purbey, Sunita Singh, Dimple Notani, P. Pavan Kumar, Amita S. Limaye, and Sanjeev Galande. Acetylation-dependent interaction of satb1 and ctbp1 mediates transcriptional repression by satb1. Molecular and Cellular Biology, 29(5):1321–1337, March 2009. URL: http://dx.doi.org/10.1128/MCB.00822-08, doi:10.1128/mcb.00822-08. This article has 88 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.00822-08)

[6. (Kohwi-Shigematsu2013Genome) Terumi Kohwi-Shigematsu, Krzysztof Poterlowicz, Ellen Ordinario, Hye-Jung Han, Vladimir A. Botchkarev, and Yoshinori Kohwi. Genome organizing function of satb1 in tumor progression. Seminars in Cancer Biology, 23(2):72–79, April 2013. URL: http://dx.doi.org/10.1016/j.semcancer.2012.06.009, doi:10.1016/j.semcancer.2012.06.009. This article has 133 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.semcancer.2012.06.009)

[7. (Naik2018SATB) Rutika Naik and Sanjeev Galande. Satb family chromatin organizers as master regulators of tumor progression. Oncogene, 38(12):1989–2004, November 2018. URL: http://dx.doi.org/10.1038/s41388-018-0541-4, doi:10.1038/s41388-018-0541-4. This article has 51 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/s41388-018-0541-4)

[8. (Yamasaki2007Structural) Kazuhiko Yamasaki, Toshihiko Akiba, Tomoko Yamasaki, and Kazuaki Harata. Structural basis for recognition of the matrix attachment region of dna by transcription factor satb1. Nucleic Acids Research, 35(15):5073–5084, July 2007. URL: http://dx.doi.org/10.1093/nar/gkm504, doi:10.1093/nar/gkm504. This article has 55 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkm504)

[9. (Frömberg2018The) Anja Frömberg, Kurt Engeland, and Achim Aigner. The special at-rich sequence binding protein 1 (satb1) and its role in solid tumors. Cancer Letters, 417:96–111, March 2018. URL: http://dx.doi.org/10.1016/j.canlet.2017.12.031, doi:10.1016/j.canlet.2017.12.031. This article has 29 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.canlet.2017.12.031)

[10. (Tan2010Phosphorylation-Dependent) Joseph-Anthony T. Tan, Jing Song, Yuan Chen, and Linda K. Durrin. Phosphorylation-dependent interaction of satb1 and pias1 directs sumo-regulated caspase cleavage of satb1. Molecular and Cellular Biology, 30(11):2823–2836, June 2010. URL: http://dx.doi.org/10.1128/MCB.01603-09, doi:10.1128/mcb.01603-09. This article has 50 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.01603-09)

[11. (Wang2014Crystal) Zheng Wang, Xue Yang, Shuang Guo, Yin Yang, Xun-Cheng Su, Yuequan Shen, and Jiafu Long. Crystal structure of the ubiquitin-like domain-cut repeat-like tandem of special at-rich sequence binding protein 1 (satb1) reveals a coordinating dna-binding mechanism. Journal of Biological Chemistry, 289(40):27376–27385, October 2014. URL: http://dx.doi.org/10.1074/jbc.m114.562314, doi:10.1074/jbc.m114.562314. This article has 27 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m114.562314)

[12. (Al‐Sohaily2014Loss) Sam Al‐Sohaily, Christopher Henderson, Christina Selinger, Laurent Pangon, Eva Segelov, Maija R. J. Kohonen‐Corish, and Janindra Warusavitarne. Loss of special <scp>at</scp>‐rich sequence‐binding protein 1 (<scp>satb</scp>1) predicts poor survival in patients with colorectal cancer. Histopathology, 65(2):155–163, May 2014. URL: http://dx.doi.org/10.1111/his.12295, doi:10.1111/his.12295. This article has 31 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/his.12295)

[13. (Wei2018Cancer-associated) Lusheng Wei, Huilin Ye, Guolin Li, Yuanting Lu, Quanbo Zhou, Shangyou Zheng, Qing Lin, Yimin Liu, Zhihua Li, and Rufu Chen. Cancer-associated fibroblasts promote progression and gemcitabine resistance via the sdf-1/satb-1 pathway in pancreatic cancer. Cell Death &amp; Disease, October 2018. URL: http://dx.doi.org/10.1038/s41419-018-1104-x, doi:10.1038/s41419-018-1104-x. This article has 101 citations.](https://doi.org/10.1038/s41419-018-1104-x)

[14. (Fessing2011p63) Michael Y. Fessing, Andrei N. Mardaryev, Michal R. Gdula, Andrey A. Sharov, Tatyana Y. Sharova, Valentina Rapisarda, Konstantin B. Gordon, Anna D. Smorodchenko, Krzysztof Poterlowicz, Giustina Ferone, Yoshinori Kohwi, Caterina Missero, Terumi Kohwi-Shigematsu, and Vladimir A. Botchkarev. P63 regulates satb1 to control tissue-specific chromatin remodeling during development of the epidermis. Journal of Cell Biology, 194(6):825–839, September 2011. URL: http://dx.doi.org/10.1083/jcb.201101148, doi:10.1083/jcb.201101148. This article has 146 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1083/jcb.201101148)

[15. (Agrelo2009SATB1) Ruben Agrelo, Abdallah Souabni, Maria Novatchkova, Christian Haslinger, Martin Leeb, Vukoslav Komnenovic, Hiroyuki Kishimoto, Lionel Gresh, Terumi Kohwi-Shigematsu, Lukas Kenner, and Anton Wutz. Satb1 defines the developmental context for gene silencing by xist in lymphoma and embryonic cells. Developmental Cell, 16(4):507–516, April 2009. URL: http://dx.doi.org/10.1016/j.devcel.2009.03.006, doi:10.1016/j.devcel.2009.03.006. This article has 154 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.devcel.2009.03.006)

[16. (GlatzelPlucińska2019The) Natalia Glatzel-Plucińska, Aleksandra Piotrowska, Piotr Dzięgiel, and Marzenna Podhorska-Okołów. The role of satb1 in tumour progression and metastasis. International Journal of Molecular Sciences, 20(17):4156, August 2019. URL: http://dx.doi.org/10.3390/ijms20174156, doi:10.3390/ijms20174156. This article has 28 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms20174156)

[17. (Purbey2008PDZ) Prabhat Kumar Purbey, Sunita Singh, P. Pavan Kumar, Sameet Mehta, K. N. Ganesh, Debashis Mitra, and Sanjeev Galande. Pdz domain-mediated dimerization and homeodomain-directed specificity are required for high-affinity dna binding by satb1. Nucleic Acids Research, 36(7):2107–2122, January 2008. URL: http://dx.doi.org/10.1093/nar/gkm1151, doi:10.1093/nar/gkm1151. This article has 65 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkm1151)