High Mobility Group A1 Chromatin Regulators in Colon Carcinogenesis

摘要 背景：我们建议阐明高迁移率基团A1介导的分子机制 (HMGA1)染色质重塑蛋白在结直肠癌发生中的作用。HMGA1基因是高度 在胚胎发育过程中表达，但在大多数成体组织中在出生后沉默。HMGA1也是 在不同的低分化癌症中过度表达和高水平预示着不良结果。HMGA1 蛋白质通过“打开”染色质和将转录复合体招募到DNA来调节基因的表达。 虽然染色质调节器显然有助于管理核架构和细胞命运决定，但 人们对潜在的机制知之甚少。在这里，我们重点介绍HMGA1在结直肠癌(CRC)中的作用。 我们关于HMGA1促进结直肠癌肿瘤进展的科学假设基于以下初步结论 结果：1)HMGA1在结直肠癌中高表达，与非恶性结肠上皮相比，2) 沉默HMGA1阻断致癌特性，防止转移进展，并耗尽癌症干 临床前结直肠癌模型中的细胞，3)在转基因小鼠中，HMGA1过表达：a)诱导过度增殖， 小肠和大肠的异常隐窝形成和癌前息肉病，以及，b)扩张小肠 肠道干细胞(ISC)池通过放大Wnt信号(Xian等人，《自然通讯》；2017)，5)令人惊讶地， HMGA1还通过诱导Sox9产生Paneth细胞来帮助“建立”干细胞利基，Paneth细胞支持和 培养小ISCs，6)HMGA1和SOX9在人结肠上皮和两者中呈正相关 结肠癌中显著上调，以及，7)炎症信号和致癌细菌 与HMGA1在临床前肿瘤模型中的表达相关。 总之，这些耐人寻味的结果支持以下假设：1)正常情况下需要HMGA1 结肠上皮中的干细胞功能和组织动态平衡，2)去调控的HMGA1破坏这一点 通过染色质结构的异常变化平衡并推动癌症的发生和肿瘤的进展 3)炎症信号和特定的致癌菌诱导HMGA1驱动 肿瘤进展，以及，4)识别与HMGA1过度表达有关的机制将揭示新的途径 这可以被调节来治疗甚至预防结肠癌的发生。 目的/方法：为了测试这一点，我们提出了以下具体目标：1)定义致癌细胞和干细胞 依赖于HMGA1的结肠上皮表型，2)阐明表观遗传学改变和遗传 HMGA1在致癌过程中发挥作用的途径，以及，3)确定靶向 在临床前模型中，HMGA1在减轻或预防结肠癌发生方面是有效的。 影响：我们希望阐明诱导HMGA1的机制以及受控制的下游途径 由CRC中的HMGA1。这项工作可能揭示结肠癌发病机制的新范式，并导致 治疗甚至预防这种可怕癌症的新方法。

ABSTRACT Background: We propose to elucidate molecular mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin remodeling proteins during colorectal carcinogenesis. The HMGA1 gene is highly expressed during embryogenesis, but silenced postnatally in most adult tissues. HMGA1 is also overexpressed in diverse, poorly differentiated cancers and high levels portend adverse outcomes. HMGA1 proteins modulate gene expression by “opening” chromatin and recruiting transcriptional complexes to DNA. While it is clear that chromatin regulators help to govern nuclear architecture and cell fate decisions, the underlying mechanisms are poorly understood. Here, we focus on HMGA1 in colorectal cancer (CRC). Our scientific premise that HMGA1 fosters tumor progression in CRC is based on the following preliminary results: 1) HMGA1 is highly overexpressed in CRC compared to non-malignant colonic epithelium, 2) Silencing HMGA1 blocks oncogenic properties, prevents metastatic progression, and depletes cancer stem cells in preclinical CRC models, 3) In transgenic mice, Hmga1 overexpression: a) induces hyperproliferation, aberrant crypt formation, and premalignant polyposis in small and large intestines, and, b) expands the small intestinal stem cell (ISC) pool by amplifying Wnt signals (Xian et al, Nature Comm; 2017), 5) Surprisingly, Hmga1 also helps to “build” a stem cell niche by inducing Sox9 to generate Paneth cells, which support and nurture small ISCs, 6) HMGA1 and SOX9 are positively correlated in human colon epithelium and both become markedly up-regulated in colon cancer, and, 7) Inflammatory signals and procarcinogenic bacteria associate with Hmga1 expression in preclinical tumor models. Together, these intriguing results support the following hypotheses: 1) Hmga1 is required for normal stem cell function and tissue homeostasis in colonic epithelium, 2) Deregulated HMGA1 disrupts this equilibrium and drives carcinogenesis and tumor progression through aberrant changes in chromatin structure and gene expression, 3) Inflammatory signals and specific pro-carcinogenic bacteria induce HMGA1 to drive tumor progession, and, 4) Identifying mechanisms linked to HMGA1 overexpression will reveal novel pathways that could be modulated to treat, or even prevent, colon carcinogenesis. Aims/Approach: To test this, we propose the following Specific Aims: 1) To define oncogenic and stem cell phenotypes dependent upon HMGA1 in colonic epithelium, 2) To elucidate epigenetic alterations and genetic pathways through which HMGA1 functions during carcinogenesis, and, 3) To determine whether targeting Hmga1 is effective in mitigating or preventing colon carcinogenesis in preclinical models. Impact: We expect to elucidate mechanisms that induce HMGA1 as well as downstream pathways governed by HMGA1 in CRC. This work could reveal a new paradigm for colon cancer pathogenesis and lead to novel approaches to treat, or even prevent, this formidable cancer.