Oncotarget

Research Papers:

The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

Mark P. Labrecque, Mandeep K. Takhar, Rebecca Nason, Stephanie Santacruz, Kevin J. Tam, Shabnam Massah, Anne Haegert, Robert H. Bell, Manuel Altamirano-Dimas, Colin C. Collins, Frank J.S. Lee, Gratien G. Prefontaine, Michael E. Cox and Timothy V. Beischlag _

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Oncotarget. 2016; 7:24284-24302. https://doi.org/10.18632/oncotarget.8301

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Abstract

Mark P. Labrecque1, Mandeep K. Takhar1, Rebecca Nason1, Stephanie Santacruz1, Kevin J. Tam1,2, Shabnam Massah1, Anne Haegert2, Robert H. Bell2, Manuel Altamirano-Dimas2, Colin C. Collins2, Frank J.S. Lee1, Gratien G. Prefontaine1, Michael E. Cox2, Timothy V. Beischlag1

1The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

2Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence to:

Timothy V. Beischlag, e-mail: tvb@sfu.ca

Keywords: hypoxia, retinoblastoma protein, invasion, neuroendocrine differentiation, prostate cancer

Received: October 23, 2015     Accepted: March 04, 2016     Published: March 23, 2016

ABSTRACT

Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.


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