S-Adenosylhomocysteine Hydrolase Downregulation Contributes to Tumorogenesis
J Hernandez-Losa, M Lleonart, A Carnero, R Somoza, S Ramon y Cajal. Hospital University Vall d Hebron, Barcelona, Spain; Spanish National Cancer Research Center (CNIO), Madrid, Spain;Madrid, Spain
Background: With an aim to discover novel genes involved in cell proliferation, a genome-wide loss-of-function genetic screen was performed to identify additional putative tumor suppressor genes. To date, five genes have been identified from differing biochemical families. In this project, one of these genes was focused on, namely S-Adenosylhomocysteine hydrolase (SAHH), and its role in human tumors.
Design: The SAHH gene function was characterized in MEFs. The expression of SAHH was overexpress with cDNA and downregulart with siRNA. Cell proliferation was analyzed by the Crystal Violet method, and -galactosidase activity was performed to identify the senescent cells. In human tumors, the level of expression of SAHH was studied in a cancer profiling array with 206 samples of varying tumors using real-time PCR. We corroborate the results in a set of 40 patients with colorectal tumors by real-time PCR and Western-Blot. Both the normal and tumoral samples of each patient were evaluated.
Results: The in-vitro results show that SAHH inactivation confers resistance to both p53 and p16INK4-induced proliferation arrest. Interestingly, SAHH inactivation inhibits p53 transcriptional activity and impairs DNA damage-induced transcription of p21Cip1. Moreover, SAHH downregulation modulates senescence in primary cells. In human tumors SAHH mRNA was lost in 50% of tumor tissues tested, including up to 15 different types in comparison to normal tissue counterparts. Moreover, SAHH protein was also affected in some colon cancers.
Conclusions: With these results we propose that SAHH a gen related with the turnover of adenosine, and homocysteine is downregulated in a large number of tumors and may represent an important novel tumor-supresor gene.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 245, Tuesday Morning