- Main
p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas
- Hsieh, Meng-Hsiung;
- Choe, Joshua H;
- Gadhvi, Jashkaran;
- Kim, Yoon Jung;
- Arguez, Marcus A;
- Palmer, Madison;
- Gerold, Haleigh;
- Nowak, Chance;
- Do, Hung;
- Mazambani, Simbarashe;
- Knighton, Jordan K;
- Cha, Matthew;
- Goodwin, Justin;
- Kang, Min Kyu;
- Jeong, Ji Yun;
- Lee, Shin Yup;
- Faubert, Brandon;
- Xuan, Zhenyu;
- Abel, E Dale;
- Scafoglio, Claudio;
- Shackelford, David B;
- Minna, John D;
- Singh, Pankaj K;
- Shulaev, Vladimir;
- Bleris, Leonidas;
- Hoyt, Kenneth;
- Kim, James;
- Inoue, Masahiro;
- DeBerardinis, Ralph J;
- Kim, Tae Hoon;
- Kim, Jung-whan
- et al.
Published Web Location
https://doi.org/10.1016/j.celrep.2019.07.027Abstract
Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.
Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
Main Content
Enter the password to open this PDF file:
-
-
-
-
-
-
-
-
-
-
-
-
-
-