TMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer

Renal cell carcinoma (RCC) is a high-risk metastasizing tumor with a poor prognosis and poorly understood mechanism. In this study, we demonstrate that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is a novel tumor suppressor that is highly expressed in normal renal tubular epithelial cells, but it is downregulated in human renal cancer. We have identified CCAAT/enhancer-binding proteinβ (C/EBPβ, also called LAP) as a key transcriptional regulator of TMIGD1, whose loss of expression is responsible for downregulation of TMIGD1 in RCC. Transcriptionally active C/EBPβ/LAP physically interacted with and increased TMIGD1 promoter activity and expression of TMIGD1. Re-introduction of TMIGD1 into renal tumor cells significantly inhibited tumor growth and metastatic behaviors such as morphogenic branching and cell migration. Restoring TMIGD1 expression in renal tumor cells stimulated phosphorylation of p38MAK, induced expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in regulation of the cell cycle. The present study identifies TMIGD1 as a novel candidate tumor suppressor gene and provides important insight into pathobiology of RCC that could lead to a better diagnosis and possible novel therapy for RCC.