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The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis

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Abstract

Increased abundance of proto-oncogene AKT and reduced expression of tumor suppressor Forkhead box O3 (FOXO3a), the downstream target of AKT, is frequent in carcinogenesis. Mechanistic insights of AKT gene regulation are limited. DEAD box RNA helicase p68 is overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. Here, we report a novel mechanism of p68-mediated transcriptional activation of AKT, and its ensuing effect on FOXO3a, in colon carcinogenesis. Interestingly, we found that the expression of p68 and AKT exhibits strong positive correlation in normal and colon carcinoma patient samples. In addition, p68 increased both AKT messenger RNA (mRNA) and protein, enhanced AKT promoter activity in multiple colon cancer cell lines. Conversely, p68 knockdown led to reduced AKT mRNA and protein, diminished AKT promoter activity. Here, we demonstrated that p68 occupies AKT promoter with β-catenin as well as nuclear factor-κB (NF-κB)and cooperates with these in potentiating AKT transcription. Furthermore, p68 and FOXO3a expression followed inverse correlation in the same set of colon carcinoma samples. We observed that p68 significantly reduced FOXO3a protein level in an AKT-dependent manner. Studies in primary tumors and metastatic lung nodules generated in mice colorectal allograft model, using syngeneic cells stably expressing p68, corroborated our in vitro findings. Hence, a new mechanism of oncogenesis is attributed to p68 by upregulation of AKT and consequent nuclear exclusion and degradation of tumor suppressor FOXO3a.

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Acknowledgements

We thank Dr Frances V Fuller-Pace, Dr KM Yamada and Dr B Alman for gifting us the pGS5-p68 construct, pGZ21dx vector and pBI-β-catenin construct, respectively; Dr Uttara Chatterjee (Park Clinic, Kolkata, India) for providing human normal colon and colon carcinoma samples, associated pathological reports and helping in analysis of the related data; Dr Samit Adhya for kindly providing us the facility for animal lung imaging. This work is supported by grants from CSIR, India (EMPOWER-OLP-002, MEDCHEM-BSC0108 and CSIR-MAYO: MLP-0017).

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Author notes

  1. V Khare and K K N Guturi: These authors contributed equally to the work.

Authors and Affiliations

  1. Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India

    M Sarkar, V Khare, K K N Guturi, N Das & M K Ghosh

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  1. M Sarkar
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  2. V Khare
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  3. K K N Guturi
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Correspondence to M K Ghosh.

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Sarkar, M., Khare, V., Guturi, K. et al. The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis. Oncogene 34, 5843–5856 (2015). https://doi.org/10.1038/onc.2015.42

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