某些恶性肿瘤的沉默基因可抗癌

　　耶鲁大学癌症研究中心的研究人员在新研究中表明，某些恶性肿瘤的沉默基因或许可以帮助抑制肿瘤的发生。这项研究提示，可通过干扰基因沉默的过程来增加恶性肿瘤对癌症疗法产生反应的时间和机会。相关文章发表于2014年7月17日的《Cell Reports》杂志上。

　　随着癌症的发育，正常的血液供给慢慢不能满足其需求，因此过度生长的肿瘤组织吸收的氧气量就会比正常组织少，这种低氧环境称之为缺氧状态，缺氧状态往往和不同类型的恶性肿瘤的发生相关。

　　这项研究中研究人员利用结肠癌组织进行研究发现，缺氧条件可以诱发关键的肿瘤抑制基因MLH1发生沉默;与此同时研究人员也发现了一种名为LSD1的酶类，这种酶是一种赖氨酸特殊的脱甲基酶，酶类LSD1连同MLH1都可以作为逆转或者阻断沉默过程的靶点;由于LSD1是一种特殊酶类，因此科学家们可以利用小分子对其产生的靶向作用来抑制其活性。

　　研究者Peter M. Glazer博士表示，长期以来我们一直知道含氧量低的肿瘤组织和较差的预后直接相关，但是含氧量低的肿瘤中往往也会发生某些特殊基因的沉默，这未必就是一件坏事;如今我们知道了缺氧状态在诱发肿瘤恶化中的分子机制，下一步我们将通过更为深入的研究来解释缺氧条件影响其它肿瘤抑制基因的分子机制。(来源：生物帮)

　　原文摘要：

Silencing of the DNA Mismatch Repair Gene MLH1 Induced by Hypoxic Stress in a Pathway Dependent on the Histone Demethylase LSD1

Yuhong Lu, Narendra Wajapeyee, Mitchell S. Turker, Peter M. Glazer

　　Silencing of MLH1 is frequently seen in sporadic colorectal cancers. We show here that hypoxia causes decreased histone H3 lysine 4 (H3K4) methylation at the MLH1 promoter via the action of the H3K4 demethylases LSD1 and PLU-1 and promotes durable long-term silencing in a pathway that requires LSD1. Knockdown of LSD1 or its corepressor, CoREST, also prevents the resilencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer Cells following transient reactivation by treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC). The results demonstrate that hypoxia is a driving force for silencing of MLH1 and that the LSD1/CoREST complex is necessary for this process. The results reveal a mechanism by which hypoxia promotes cancer cell evolution to drive malignant progression through epigenetic modulation. Our findings suggest that LSD1/CoREST acts as a colon cancer oncogene by epigenetically silencing MLH1 and also identify the LSD1/CoREST complex as a potential target for therapy.