Nuclear Proteins: Promising Targets for Cancer Drugs

Y.-   L.   Yao; W.-   M.   Yang

Abstract

Recent progress in cancer drug therapy has recognized that the nucleus of the eukaryotic cell is an active site for many cellular processes important to the development of cancer. Many of these processes take place in specialized compartments of the nucleus. One of such sub-nuclear compartments is the promyelocytic leukemia nuclear body (PML NB). In acute promyelocytic leukemia (APL), PML forms a fusion protein with the retinoic acid receptor (RAR) alpha as a result of chromosomal translocation. This PML-RAR alpha fusion protein is responsible for the proliferative and de-differentiated phenotype of the leukemic cells and is the target of all-trans retinoic acid (ATRA). Another example of the specialized sub-nuclear compartments important in the targeting of cancer is the nucleolus. Recently, it has been proposed that the nucleolus serves as a stress sensor for the cell, and the molecular mechanism underlying this proposal has been discovered. Moreover, many anti-cancer drugs target specific protein-protein interactions within the nucleus. We will discuss current development surrounding two such target proteins: the hypoxia-inducible factor 1 alpha (HIF- 1alpha) and FKBP25. Furthermore, chromatin structure, which is affected by modifications of core histones, has become a target of anti-cancer drugs. In this review, we will emphasize the significance of nuclear proteins as promising targets for cancer drug therapy by discussing a few key ideas, in three broad categories of specialized sub-nuclear compartments, protein-protein interactions, and the modifications of the chromatin structure.

Keywords: The nucleus, PML and NBs, the nucleolus, HIF-1α, FKBP25, histone acetylation/deacetylation, histone methylation/demethylation, PARP