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.