en Cancer Cancer Original Article Original Article Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial cancer occurring in the oral cavity, where it accounts for nearly 90% of all oral cavity neoplasms. The c-MYC transcription factor plays an important role in the control of programmed cell death, normal-to-malignant cellular transformation, and progression of the cell cycle. However, the role of <em>c-MYC</em> in controlling the proliferation of OSCC cells is not well known. In this study, <em>c-MYC</em> gene was silenced in OSCC cells (ORL-136T), and molecular and cellular responses were screened. To identify the pathway through which cell death occurred, cytotoxicity, colony formation, western blotting, caspase-3, and RT-qPCR analyzes were performed. Results indicated that knockdown of <em>c-MYC </em>has resulted in a significant decrease in the cell viability and c-MYC protein synthesis. Furthermore, caspase-3 was shown to be upregulated leading to apoptosis <em>via </em>the intrinsic pathway. In response to <em>c-MYC</em> knockdown, eight cell proliferation-associated genes showed variable expression profiles: <em>c-MYC</em> (-21.2), <em>p21 </em>(-2.5), <em>CCNA1</em>(1.8), <em>BCL</em>2 (-1.4), <em>p53</em>(-3.7), <em>BAX</em>(1.1), and <em>CYCS</em> (19.3)<em>. p27</em> expression was dramatically decreased in <em>c-MYC</em>-silenced cells in comparison with control, and this might indicate that the relative absence of <em>c-MYC</em> triggered intrinsic apoptosis in OSCC cells <em>via p27 </em>and<em> CYCS</em>. Oral squamous cell carcinoma, siRNA, c-MYC, knockdown, p27, CYCS 45 55 http://ijmcmed.org/browse.php?a_code=A-10-3084-1&slc_lang=en&sid=1 Hussein Sabit hhsabit@iau.edu.sa 100319475328460020446 100319475328460020446 No Department of Genetics, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. Huseyin Tombuloglu htoglu@iau.edu.sa 100319475328460020447 100319475328460020447 Yes Department of Genetics, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. Emre Cevik ecevik@iau.edu.sa 100319475328460020448 100319475328460020448 No Department of Genetics, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. Shaimaa Abdel-Ghany Shaimaa.ibraheem@must.edu.eg 100319475328460020449 100319475328460020449 No College of Biotechnology, Misr University for Science and Technology, Giza, Egypt. Engy El-Zawahri engy.mokhtar@must.edu.eg 100319475328460020450 100319475328460020450 No College of Biotechnology, Misr University for Science and Technology, Giza, Egypt. Amr El-Sawy dr.amrelsawi@gmail.com 100319475328460020451 100319475328460020451 No College of Biotechnology, Misr University for Science and Technology, Giza, Egypt. Sevim Isik sevim.isik@uskudar.edu.tr 100319475328460020452 100319475328460020452 No Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey. Ebtesam Alsuhaimi eabtesam@iau.edu.sa 100319475328460020453 100319475328460020453 No Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.