Oncogenes can drive tumor formation whereas activation of oncogene in normal cells causes cell growth arrest, termed oncogene-induced senescence (OIS), which acts as a barrier to tumor formation. Understanding how OIS is maintained in non-transformed cells and how it is subverted in cancer cells is a fundamental question in cancer biology. Despite cell growth arrest, the senescent cells remain metabolically active. These metabolic alterations may be necessary for stable senescence-associated cell growth arrest, and overcoming these shifts in metabolism may cause senescence-bypass and lead to tumorigenesis. From a high throughput genomic screen, we identified several metabolism-associated genes as the potential key regulators of OIS. Particularly cysteine metabolism pathway is implicated to play a critical role in maintenance of senescence-associated cell growth arrest. We demonstrated that depletion of CBS (cystathionine-beta-synthase), a key enzyme catalyzing the conversion of homocysteine and serine to cystathione and involving in H2S and glutathione formation, rescued BJ human foreskin fibroblast cells from growth arrest induced by oncogene-activation. Further investigation of these metabolic alterations during OIS will provide more insights into OIS and OIS bypass during tumorigenesis.