Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression.
Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression.
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DOI：
10.1158/0008-5472.can-17-3045
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发表时间：
2018-04-15
期刊：
影响因子：
11.2
通讯作者：
Xian L
中科院分区：
文献类型：
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作者：
Resar L;Chia L;Xian L
高迁移率族A1(HMGA1)染色质重塑蛋白在侵袭性癌症和干细胞中丰富，尽管到目前为止，它们在这些环境中的共同功能仍然难以捉摸。最近在小鼠肠道干细胞(ISC)中的研究表明，HMGA1通过诱导表达Wnt激动剂受体和Wnt效应的基因，通过放大Wnt信号来促进自我更新。令人惊讶的是，HMGA1还通过上调Sox9来“建立”干细胞生态位，Sox9是分化为Paneth细胞所必需的因子；这些细胞通过分泌Wnt和其他支持ISCs的因子构成上皮生态位。与非恶性上皮相比，HMGA1在结肠癌中也高度上调，SOX9在结肠癌发生过程中过度表达。有趣的是，HMGA1在多种结果不佳的癌症中过度表达，在这些癌症中，它调节发育基因。同样，HMGA1诱导胚胎干细胞中负责多能性和自我更新的基因。这些发现表明，HMGA1维持Wnt和其他发育转录网络，并表明HMGA1过表达通过这些途径的失调促进癌症发生和肿瘤进展。现在需要研究更准确地确定HMGA1如何调节染色质结构以放大发育基因，以及如何在癌症治疗中破坏这一过程。
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing selfrenewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also “builds” a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are nowneeded to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy.