Jae Young Hur1,2, Hyeong Ryul Kim3, Jung Yeon Lee4, Sojung Park5, Ji An Hwang5, Woo Sung Kim5, Shinkyo Yoon6, Chang-Min Choi5,6, Jin Kyung Rho7, Jae Cheol Lee8. 1. Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea. 2. Lung Cancer Center & Department of Pathology, Konkuk University Medical Center, Seoul, South Korea. 3. Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea. 4. Department of Internal Medicine, Graduate School, Chungbuk National University, Cheongju, South Korea. 5. Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea. 6. Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. 7. Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. jkrho@amc.seoul.kr. 8. Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. jclee@amc.seoul.kr.
Abstract
PURPOSE: Despite the development of molecular targeted therapies, few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. Here, we investigated the effects of THZ1, a potent cyclin-dependent kinase 7 (CDK7) inhibitor that plays a key role in gene transcription, in SCC. METHODS: Lung SCC-derived cell viabilities were assessed using a CCK-8 assay. SOX2 expression and RNAPII-CTD phosphorylation levels after THZ1 treatment were determined by Western blotting. The effect of SOX2 suppression using shRNA was assessed by flow cytometry. Gene expression patterns after THZ1 treatment of lung SCC-derived cells were identified using microarray-based mRNA profiling. RESULTS: We found that THZ1 treatment led to suppression of cell growth and apoptotic cell death in SOX2-amplified SCC-derived cells only, whereas the modest growth-inhibitory effect of cisplatin did not differ according to SOX2 amplification status. We also found that THZ1 decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II and the expression of several genes. Specifically, we found that the expression of transcription-associated genes, including SOX2, was down-regulated by THZ1 in SOX2-amplified SCC cells. This inhibition of SOX2 expression resulted in suppression of the growth of these cells. CONCLUSIONS: From our data, we conclude that THZ1 may effectively control the proliferation and survival of SOX2-amplified SCC cells through a decrease in global transcriptional activity, suggesting that CDK7 inhibition leading to transcription suppression may be a promising therapeutic option for lung SCC with a SOX2 amplification.
PURPOSE: Despite the development of molecular targeted therapies, few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. Here, we investigated the effects of THZ1, a potent cyclin-dependent kinase 7 (CDK7) inhibitor that plays a key role in gene transcription, in SCC. METHODS: Lung SCC-derived cell viabilities were assessed using a CCK-8 assay. SOX2 expression and RNAPII-CTD phosphorylation levels after THZ1 treatment were determined by Western blotting. The effect of SOX2 suppression using shRNA was assessed by flow cytometry. Gene expression patterns after THZ1 treatment of lung SCC-derived cells were identified using microarray-based mRNA profiling. RESULTS: We found that THZ1 treatment led to suppression of cell growth and apoptotic cell death in SOX2-amplified SCC-derived cells only, whereas the modest growth-inhibitory effect of cisplatin did not differ according to SOX2 amplification status. We also found that THZ1 decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II and the expression of several genes. Specifically, we found that the expression of transcription-associated genes, including SOX2, was down-regulated by THZ1 in SOX2-amplified SCC cells. This inhibition of SOX2 expression resulted in suppression of the growth of these cells. CONCLUSIONS: From our data, we conclude that THZ1 may effectively control the proliferation and survival of SOX2-amplified SCC cells through a decrease in global transcriptional activity, suggesting that CDK7 inhibition leading to transcription suppression may be a promising therapeutic option for lung SCC with a SOX2 amplification.
Authors: Md Sohail Akhtar; Martin Heidemann; Joshua R Tietjen; David W Zhang; Rob D Chapman; Dirk Eick; Aseem Z Ansari Journal: Mol Cell Date: 2009-05-15 Impact factor: 17.970
Authors: Adam J Bass; Hideo Watanabe; Craig H Mermel; Soyoung Yu; Sven Perner; Roel G Verhaak; So Young Kim; Leslie Wardwell; Pablo Tamayo; Irit Gat-Viks; Alex H Ramos; Michele S Woo; Barbara A Weir; Gad Getz; Rameen Beroukhim; Michael O'Kelly; Amit Dutt; Orit Rozenblatt-Rosen; Piotr Dziunycz; Justin Komisarof; Lucian R Chirieac; Christopher J Lafargue; Veit Scheble; Theresia Wilbertz; Changqing Ma; Shilpa Rao; Hiroshi Nakagawa; Douglas B Stairs; Lin Lin; Thomas J Giordano; Patrick Wagner; John D Minna; Adi F Gazdar; Chang Qi Zhu; Marcia S Brose; Ivan Cecconello; Ulysses Ribeiro; Suely K Marie; Olav Dahl; Ramesh A Shivdasani; Ming-Sound Tsao; Mark A Rubin; Kwok K Wong; Aviv Regev; William C Hahn; David G Beer; Anil K Rustgi; Matthew Meyerson Journal: Nat Genet Date: 2009-10-04 Impact factor: 38.330