NKX3.1: MULTIFUNCTIONAL HOMEODOMAIN PROTEIN AND PROSTATE TUMOR SUPPRESSOR

Abstract

NKX3.1 is a developmental regulatory protein with roles in prostate epithelial differentiation and adult organ maintenance. During development, NKX3.1 is expressed from the earliest stages of prostate formation. In adults, NKX3.1 controls normal differentiation and protects against oxidative damage by regulating gene expression through interactions with other transcription factors. The loss of this protein leads to carcinogenesis, and studies have provided insight to the mechanisms by which NKX3.1 loss of function is linked to mechanisms of carcinogenesis. In prostate cancer, NKX3.1 protein levels are markedly reduced. The reduction can be attributed to mechanisms that lead to loss of a gene copy, decreased gene expression, or increased protein degradation. Down-regulation of NKX3.1 protein has significant effects on the proliferation, differentiation, and polarity of prostate epithelial cell proliferation. Furthermore, the loss of NKX3.1 increases susceptibility to DNA damage, thereby increasing oncogenic risk. Because NKX3.1 is haploinsufficient, alterations in protein levels can affect cell phenotype. Steady state NKX3.1 protein turnover is mediated to a large part by phosphorylation due to the kinase DYRK1B. Therefore, a possible mechanism for affecting NKX3.1 protein levels and prostate cancer phenotype is via kinase inhibition of DYRK1B.