The long QT syndrome gene human ether-a-go-go related gene (HERG) encodes a K(+) channel critical to cardiac repolarization. It peculiarly overexpresses in cancer cells of different histogenesis and promotes tumorigenesis. To decipher the molecular mechanisms for HERG overexpression, we identified and characterized the promoter region of the HERG gene, which contains cis-elements for multiple oncoproteins and tumor suppressors. Oncoprotein Sp1 was found to be essential to driving the HERG promoter thereby transcription. Another oncoprotein NF-kappaB transactivated, while tumor suppressor Nkx3.1 repressed HERG promoter activity and endogenous HERG transcription. Loss-of-function mutations in the corresponding cis-elements rendered a loss of the ability of the oncoproteins Sp1 and NF-kappaB to transactivate, and of the tumor repressor Nkx3.1 to repress, HERG transcription. Either activation of Sp1 and NF-kappaB or silencing of Nkx3.1 promoted tumor cell growth, and the effects were abrogated by HERG inhibition or knockdown, but facilitated by overexpression of HERG, indicating that HERG mediates the cell growth signals generated by activation of oncoproteins or inactivation of tumor suppressors. Binding of Sp1, NF-kappaB, and Nkx3.1 to their respective cis-elements in the HERG promoter in vitro and their presence on the HERG promoter in vivo were confirmed. Therefore, the HERG promoter region is characterized by multiple Sp1 binding sites that are responsible for transcription initiation of the HERG gene and by binding sites for multiple other oncogenes and tumor suppressor genes being important for regulating HERG expression. The HERG K(+) channel is likely a mediator of growth-promoting processes induced by oncoproteins and/or by silencing of tumor suppressors.