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Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression

Oncogene volume 35, pages 1679–1691 (2016)Cite this article

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Abstract

The chromatin organizer SATB1 has been implicated in the development and progression of multiple cancers including breast and colorectal cancers. However, the regulation and role of SATB1 in colorectal cancers is poorly understood. Here, we demonstrate that expression of SATB1 is induced upon hyperactivation of Wnt/β-catenin signaling and repressed upon depletion of TCF7L2 (TCF4) and β-catenin. Using several colorectal cancer cell line models and the APC min mutant zebrafish in vivo model, we established that SATB1 is a novel target of Wnt/β-catenin signaling. We show that direct binding of TCF7L2/β-catenin complex on Satb1 promoter is required for the regulation of SATB1. Moreover, SATB1 is sufficient to regulate the expression of β-catenin, members of TCF family, multiple downstream effectors and mediators of Wnt pathway. SATB1 potentiates the cellular changes and expression of key cancer-associated genes in non-aggressive colorectal cells, promotes their aggressive phenotype and tumorigenesis in vivo. Conversely, depletion of SATB1 from aggressive cells reprograms the expression of cancer-associated genes, reverses their cancer phenotype and reduces the potential of these cells to develop tumors in vivo. We also show that SATB1 and β-catenin bind to the promoters of TCF7L2 and the downstream targets of Wnt signaling and regulate their expression. Our findings suggest that SATB1 shares a feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt signaling-dependent regulation of β-catenin. Collectively, these results provide unequivocal evidence to establish that SATB1 reprograms the expression of tumor growth- and metastasis-associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling critical for colorectal cancer tumorigenesis.

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Acknowledgements

We thank the staff of the experimental animal facility and in vivo imaging facility of NCCS. Work was supported by grants from the Centre of Excellence in Epigenetics program of the Department of Biotechnology and the Swarnajayanti Fellowship from the Department of Science and Technology, Government of India to SG. RM is supported by fellowship from the University Grants Commission, India. We thank Mahendra Sonawane for providing RNA and whole cell lysates from APC min mutant Zebrafish.

Author contributions

R Mir and SG conceived project and designed experiments. Experiments are performed by R Mir and SP. Tissue resources are provided by PP and RM. Manuscript is written by R Mir and SG.

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Authors and Affiliations

  1. Indian Institute of Science Education and Research, Pashan, Pune, India

    R Mir, S J Pradhan & S Galande

  2. Tata Memorial Hospital, Parel, Mumbai, India

    P Patil

  3. Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai, India

    R Mulherkar

  4. National Centre for Cell Science, Pune, India

    S Galande

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Correspondence to S Galande.

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Mir, R., Pradhan, S., Patil, P. et al. Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression. Oncogene 35, 1679–1691 (2016). https://doi.org/10.1038/onc.2015.232

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