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PAWR as a Direct SRC-1/HOXC11 Suppression Target

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Tumor Suppressor Par-4

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Abstract

Regulation of cell fate is controlled through complex and highly regulated transcription of key genes including growth factors, pluripotency, cell differentiation and apoptotic genes. Dysregulation of this process in cancer is central to tumour cell plasticity, the ability of the cancer to resist drug treatment and adaptation to new metastatic environments. The p160 family of coactivator proteins, including SRC-1, are known to partner with nuclear receptor proteins to promote gene transcription and enhance cell growth. More recently, SRC-1 has also been shown to associate with other transcription factors including the homeobox protein HOXC11 to activate pluripotency and development genes. The HOXC11/SRC-1 partnership can also repress gene expression. SRC-1 has been shown to utilise the DNA methylation machinery to silence cancer cell differentiation genes including CD24, NTRK2, NR2F2, CTDP1, SETBP1, and POU3F2. Prostate apoptosis response-4 (Par-4, PAWR) is an apoptotic gene associated with prolonged disease-free survival in breast cancer patients. HOXC11-SRC-1 can utilise the histone demethylase, jumonji domain containing 2C (JMJD2C) to recruit the histone deacetylating protein HDAC1 and histone H3 lysine 27 trimethylation to silence PAWR and promote cancer cells survival in the advanced setting. Master transcriptional regulatory machinery can cooperate to aberrantly silence PAWR, to inhibit mechanisms of controlled cell death and provide a survival advantage for cancer cells.

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Authors and Affiliations

  1. Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland

    Damir Varešlija & Leonie Young

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  1. Damir Varešlija
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  2. Leonie Young
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Correspondence to Leonie Young .

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  1. Associate Director, Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    Vivek M. Rangnekar

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Varešlija, D., Young, L. (2022). PAWR as a Direct SRC-1/HOXC11 Suppression Target. In: Rangnekar, V.M. (eds) Tumor Suppressor Par-4. Springer, Cham. https://doi.org/10.1007/978-3-030-73572-2_11

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