The Impact of Cholesterol Biosynthesis on Head and Neck Squamous Cell Carcinoma
Open Access DepositedHNSCC (Head and Neck Squamous Cell Carcinoma) is a type of cancer that originates in the squamous cells lining the mucosal surfaces of the head and neck region, including the mouth, throat (pharynx), voice box (larynx), sinuses, and nasal cavity. The biosynthetic pathways of cancer cells are different from those of normal cells.To find the difference in cancer cells biosynthesis pathway and normal cells biosynthesis pathway, the preliminary study from our laboratory used HNSCC tumors from the patients with paired normal tissues and conducted high-throughput RNA sequencing (RNA-seq) (Done by collaborators Drs. Bok-Soon Lee and Chul-Ho Kim at Ajou University Medical School, Korea). Our preliminary data identified that the altered biosynthesis pathways are cholesterol and steroid biosynthesis pathways in tumors when compared with normal tissues. However, in vitro analyses showed that exogenous cholesterol does not affect the growth and survival of HNSCC cell lines, but suggest that the up-regulated genes in the cholesterol biosynthesis pathway may support the survival or growth of HNSCC rather than produce more cholesterol. By further looking into RNA-seq data, we found that 7-dehydrocholesterol Reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) mRNA expressions are specially increased, which are responsible for the final step in cholesterol production in many types of cells. DHCR7 converts 7-dehydrocholesterol (7-DHC) to cholesterol, whereas DHCR24 converts desmosterol to cholesterol. To understand whether these two enzymes possess other functional roles in HNSCC cells, we used small inhibitors for these two enzymes and found that both DHCR7 and DHCR24 are essential to HNSCC cell’s growth and survival. To further investigate the mechanism behind this phenomenon, we treated HNSCC with the substrate of these two enzymes. We found out that 7-DHC but not desmosterol reduced cell viability. In summary, my research project indicates that the altered cholesterol biosynthesis pathway is to protect cancer cells from cell death by removing the 7-DHC accumulated in HNSCC.
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