近日一项研究发现一个众所周知的肿瘤抑制因子--pRb发挥作用的新机制。这项研究由美国伊利诺伊大学和西班牙庞培法布拉大学的科学家共同完成，发表在国际学术期刊gene and development上。
肿瘤抑制因子是一类为细胞增殖提供天然"刹车"作用的蛋白分子，能够阻止恶性肿瘤的形成。深入理解这些蛋白分子如何发挥保护性作用或成为开发肿瘤靶向治疗方法的关键。
Rb是一个有着很长研究历史的"爷爷"级肿瘤抑制因子，其最早发现于儿童视网膜母细胞瘤，也因此而得到命名。同时，它也是在人类中最早发现的肿瘤抑制基因，还是第一个在实验小鼠模型上得到成功敲除的抗癌基因。该基因编码的pRb蛋白是一个影响细胞生长，增殖，分化，与周围细胞相互作用以及适时发生细胞死亡过程的关键调控因子。
目前大部分对pRb的研究都集中在它对细胞生长和分裂过程的影响上。在这项最新研究中，研究人员发现pRb还可以通过限制一个叫做KDM5A的分子的活性抑制肿瘤发生，KDM5A是一个表观遗传修饰酶，它能够调节特定基因表达进而影响线粒体对细胞内能量的消耗作用，而许多癌细胞依赖于糖酵解过程以获得能量，降低了对线粒体的依赖性。
如果癌细胞分化程度较低，仍处于未成熟状态，那么它所形成的肿瘤也就更具侵袭性。研究人员发现如果在pRb缺失细胞内重新恢复线粒体氧化能够促进未成熟癌细胞变得更加成熟，并会降低其细胞分裂能力。
研究人员在缺失pRb的几种不同的人类癌细胞系中抑制了KDM5A的活性，每种细胞都会转变为正常代谢过程并停止细胞分裂。他们还在过度产生线粒体的细胞中看到了相同的现象。
这项研究表明肿瘤或许对代谢治疗方法特别敏感，未来或可与传统化疗方法联合使用用于癌症治疗。
Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
Renáta Váraljai1,7, Abul B.M.M.K. Islam1,2,3,7, Michael L. Beshiri1, Jalees Rehman4,5, Nuria Lopez-Bigas2,6 and Elizaveta V. Benevolenskaya1
The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.