Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Nat Med. 2011 Sep 25;17(10):1275-82. doi: 10.1038/nm.2459.
BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.
BRCA1 是一种众所周知的肿瘤抑制因子，与多种相互作用的伙伴相互作用，预计具有多种生物学功能。然而，到目前为止，其唯一确立的作用是在受损 DNA 的修复和细胞周期调控中。在这方面，对 BRCA1 的低外显率变体的病因学研究为揭示其其他生理上重要的功能提供了机会。基于这一原理，我们研究了 BRCA1 的 R1699Q 变体，这是一种潜在的中度风险变体，发现它不会损害 DNA 损伤修复，但会废除 microRNA-155（miR-155）的抑制作用，miR-155 是一种真正的致癌 miRNA。从机制上讲，我们发现 BRCA1 通过与 HDAC2 结合来抑制 miR-155 的表达，后者使 miR-155 启动子上的组蛋白 H2A 和 H3 去乙酰化。我们表明，miR-155 的过表达可加速体内肿瘤细胞系的生长，但 miR-155 的敲低可减弱其生长。我们的发现证明了 BRCA1 通过一种新的肿瘤抑制方式，并且表明 miR-155 是 BRCA1 缺陷型肿瘤的潜在治疗靶标。
