Abstract 1669: Expression of a novel zinc-finger transcription factor ZKSCAN3 in human tumors and its potential as a therapeutic target

Abstract

Abstract Previous studies from our group demonstrated that zinc finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel zinc-finger transcription factor, coordinated a gene expression program targeting Cyclin D1, Cyclin D2, NF- κB, Integrin β4, as well as VEGF and IGF-2, among others, in which these genes have been suggested to play critical roles in tumor progression. To examine if ZKSCAN3 represents a potential cancer therapeutic target, expression of ZKSCAN3 was investigated in multiple tumor types. By immunohistochemistry (IHC), we observed that ZKSCAN3 protein greatly expressed in majority tumor tissues and cells, including solid tumors (colorectal carcinoma, prostate cancer, bladder cancer, and breast cancer) and liquid malignancies (multiple myeloma, non-Hodgkin B cell lymphoma, mantle cell lymphoma, MALT, diffuse large B cell lymphoma), but not non-malignant adjacent tissues. ZKSCAN3 expression was also associated with tumor progression, evidenced by IHC staining in different stages of colorectal carcinoma and prostate cancer samples. Very interestingly, lack of ZKSCAN3 expression was observed in Hodgkin lymphoma and angioimmunoblastic T cell lymphoma, suggesting that ZKSCAN3 selectively expressed in certain tumor types. Moreover, quantitative real-time polymerase chain reaction (qPCR) was performed to verify ZKSCAN3 mRNA expression in multiple myeloma. Consistent with the IHC data, CD19+ normal B cells and CD138+ plasma cells have little expression of ZKSCAN3, meanwhile malignant plasma cells greatly expressed ZKSCAN3 gene. The differential expression pattern of ZKSCAN3 between tumor cells and non-malignant cells strongly suggests that ZKSCAN3 may play an important role in tumor pathogenesis. Indeed, in addition to the identified gene expression program that was regulated by ZKSCAN3, targeting ZKSCAN3 by its small interfering (si) RNA led to slowed tumor growth and decreased chemosensitivity, and overexpression of ZKSCAN3 greatly promoted tumor growth and enhanced chemosensitivity in the models of multiple myeloma and colon cancer, indicating that ZKSCAN3 may represent a promising cancer therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1669. doi:10.1158/1538-7445.AM2011-1669