Research Papers:

Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth

Craig S. Richmond, Darby Oldenburg, Garrett Dancik, David R. Meier, Benjamin Weinhaus, Dan Theodorescu and Sunny Guin _

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Oncotarget. 2018; 9:16718-16730. https://doi.org/10.18632/oncotarget.24676

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Craig S. Richmond1, Darby Oldenburg1, Garrett Dancik2, David R. Meier1, Benjamin Weinhaus1, Dan Theodorescu3 and Sunny Guin1

1Medical Research, Gundersen Medical Foundation, La Crosse, WI, USA

2Department of Mathematics and Computer Science, Eastern Connecticut State University, Willimantic, CT, USA

3Department of Surgery (Urology), University of Colorado, Aurora, CO, USA

Correspondence to:

Sunny Guin, email: sguin@gundersenhealth.org

Keywords: non-small cell lung cancer; hyaluronic acid; AGL; HAS2; RHAMM

Received: September 06, 2017     Accepted: February 28, 2018    Published: March 30, 2018


Glycogen debranching enzyme (AGL) and Glycogen phosphorylase (PYG) are responsible for glycogen breakdown. We have earlier shown that AGL is a regulator of bladder tumor growth. Here we investigate the role of AGL in non-small cell lung cancers (NSCLC). Short hairpin RNA (shRNA) driven knockdown of AGL resulted in increased anchorage independent and xenograft growth of NSCLC cells. We further establish that an increase in hyaluronic acid (HA) synthesis driven by Hyaluronic Acid Synthase 2 (HAS2) is critical for anchorage independent growth of NSCLC cells with AGL loss. Using gene knockdown approach against HAS2 and by using 4-methylumbelliferone (4MU), an inhibitor of HA synthesis, we show that HA synthesis is critical for growth of NSCLC cells that have lost AGL. We further show NSCLC cells without AGL expression are dependent on RHAMM for HA signaling and growth. Analysis of NSCLC patient datasets established that patients with low AGL/high HAS2 or low AGL/high RHAMM mRNA expression have poor overall survival compared to patients with high AGL/low HAS2 or high AGL/low RHAMM expression. We show for the first time that loss of AGL promotes anchorage independent growth of NSCLC cells. We further show that HAS2 driven HA synthesis and signaling via RHAMM is critical in regulating growth of these cancer cells with AGL loss. Further patients presenting with low AGL and HAS2 or RHAMM over expressing tumors might present the ideal cohort who would respond to inhibitors of HA synthesis and signaling.

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