Fumarate hydratase inactivation in renal tumors: HIF1α, NRF2, and "cryptic targets" of transcription factors

作     者：Aikseng Ooi Kyle A.Furge 

作者机构：Laboratory of Interdisciplinary Urological OncologyVan Andel Research Institute 

出 版 物：《Chinese Journal of Cancer》 (Chin. J. Cancer)

年 卷 期：2012年第31卷第9期

页      面：413-420页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：富马酸盐 转录因子 酶失活 肾肿瘤 缺氧诱导因子1 竞争性抑制 染色质结构 水合 

摘      要：Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2 (NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as cryptic targets of transcription factors. One such cryptic target is heme oxygenase I (HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).