Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China.
Pharmacol Res. 2024 Aug;206:107293. doi: 10.1016/j.phrs.2024.107293. Epub 2024 Jul 4.
Colorectal cancer (CRC) presents a complex landscape, characterized by both inter-tumor and intra-tumor heterogeneity. RUNX1, a gene implicated in modulating tumor cell growth, survival, and differentiation, remains incompletely understood regarding its impact on CRC prognosis. In our investigation, we discerned a positive correlation between elevated RUNX1 expression and aggressive phenotypes across various CRC subtypes. Notably, knockdown of RUNX1 demonstrated efficacy in restraining CRC proliferation both in vitro and in vivo, primarily through inducing apoptosis and impeding cell proliferation. Mechanistically, we unveiled a direct regulatory link between RUNX1 and cholesterol synthesis, mediated by its control over HMGCR expression. Knockdown of RUNX1 in CRC cells triggered HMGCR transcriptional activation, culminating in elevated cholesterol levels that subsequently hindered cancer progression. Clinically, heightened RUNX1 expression emerged as a prognostic marker for adverse outcomes in CRC patients. Our findings underscore the pivotal involvement of RUNX1 in CRC advancement and its potential as a therapeutic target. The unique influence of RUNX1 on cholesterol synthesis and HMGCR transcriptional regulation uncovers a novel pathway contributing to CRC progression.
结直肠癌（CRC）呈现出复杂的局面，具有肿瘤间和肿瘤内异质性。RUNX1 是一个调节肿瘤细胞生长、存活和分化的基因，但其对 CRC 预后的影响仍不完全清楚。在我们的研究中，我们发现 RUNX1 表达升高与各种 CRC 亚型的侵袭表型之间存在正相关。值得注意的是，RUNX1 的敲低在体外和体内均能有效抑制 CRC 的增殖，主要是通过诱导细胞凋亡和抑制细胞增殖。在机制上，我们揭示了 RUNX1 与胆固醇合成之间的直接调控关系，这是由其对 HMGCR 表达的控制介导的。CRC 细胞中 RUNX1 的敲低触发了 HMGCR 的转录激活，导致胆固醇水平升高，从而抑制癌症进展。临床上，RUNX1 表达升高被认为是 CRC 患者不良预后的一个预后标志物。我们的研究结果强调了 RUNX1 在 CRC 进展中的关键作用及其作为治疗靶点的潜力。RUNX1 对胆固醇合成和 HMGCR 转录调节的独特影响揭示了一条促进 CRC 进展的新途径。
