Examining the Regulation and Function of Cancer Testis Antigens

Cancer Testis Antigens (CTAs) are a class of genes whose expression is generally restricted to the testis, but are reactivated in cancer cells. The function and regulation of many CTAs are unknown, however several CTAs have been shown to impact tumor cell fitness and correlate with poor prognosis. Our lab became interested in CTAs after a pan-genomic-loss-of-function RNAi screen identified several CTAs as chemo-sensitizers. Acrosin Binding Protein (ACRBP) was identified in this screen and further analysis confirmed ACRBP's function as a microtubule stabilizer that protects cancer cells from the mitotic defects attributed to paclitaxel treatment. Because ACRBP is not expressed in normal somatic tissue, we are interested in how ACRBP is reactivated in cancer cells. In mouse spermatogonium, the ACRBP promoter is bound by Cyclic-amp Response Element Modulator (CREM) at a conserved Cyclic-amp response element (CRE). Depletion of its close family member CREB results in a loss of ACRBP expression in cancer cells, while overexpression of CREB induces ACRBP expression. Interestingly, this regulation appears to be phospho-independent and seems to apply to other CTAs. Another CTA, Chondrosarcoma Associated Genes 1, was identified by a loss-of-function RNAi proliferation screen as a supporter of melanoma cell proliferation. CSAG1 is highly expressed in Melanoma lines with little to no expression in normal tissues. Additional CSAG1 siRNA experiments have validated the screen data confirming CSAG1's involvement in melanoma cell proliferation. Additionally, CSAG1 loss-of-function reduces long-term melanoma cell viability and induces senescence in cancer cells. Consistent with this data, overexpression of CSAG1 enhances colony-forming ability in cancer cells. These data suggest that CSAG1 supports cancer cell viability. Further studies will help elucidate how CSAG1 supports tumor cell fitness. Understanding the regulation and function of CTAs may provide new insight into novel cancer therapeutics.