A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY PLoS Biology Pub Date : 2023-09-14 eCollection Date: 2023-09-01 DOI:10.1371/journal.pbio.3002256
Jiaojiao Hao, Jinsheng Huang, Chunyu Hua, Yan Zuo, Wendan Yu, Xiaojun Wu, Liren Li, Guoqing Xue, Xinyu Wan, Liyuan Ru, Ziyue Guo, Shilong Han, Wuguo Deng, Fei Lin, Wei Guo
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引用次数: 1

Abstract

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

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一种新的TOX3-WDR5-ABCG2信号轴通过加速干样性状和化疗耐药性来调节结直肠癌癌症的进展。
具有耐药性的癌症干细胞(CSCs)的根除赋予了化疗或靶向治疗后局部肿瘤控制的可能性。作为主要的耐药性标志物,ABCG2对结直肠癌癌症(CRC)的进化,特别是癌症干样性状的扩展也至关重要。迄今为止,关于ABCG2的表达调控,特别是其上游转录调控机制的知识在癌症(包括CRC)中仍然有限。在此,发现ABCG2在CRC CSCs(cCSCs)扩增和化疗耐药CRC组织中显著上调,并与CRC复发密切相关。从机制上讲,TOX3被鉴定为一种特异性转录因子,通过与ABCG2启动子区的-261至-141段结合,驱动ABCG2的表达以及随后的CCCSC扩增和化学抗性。此外,我们发现TOX3募集WDR5来促进CCCSC中ABCG2启动子处H3K4的三甲基化,这通过共同调节ABCG2的转录进一步赋予茎样性状和对CRC的化学抗性。根据这一观察结果,TOX3、WDR5和ABCG2在原位CRC小鼠模型的化疗耐药肿瘤组织中显示出异常激活,临床研究进一步证明,综合评估TOX3、WD R5和ABCG2可作为预测复发或转移CRC患者生存率的更有效策略。因此,我们的研究发现,TOX3-WDR5/ABCG2信号轴在调节CRC干细胞样特征和化疗耐药性方面发挥着关键作用,化疗与WDR5抑制剂的组合可能在ABCG2失调的肿瘤中诱导合成致死性。
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来源期刊
PLoS Biology
PLoS Biology 生物-生化与分子生物学
CiteScore
14.40
自引率
2.00%
发文量
359
审稿时长
3 months
期刊介绍: PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly. ISSN Numbers: eISSN: 1545-7885 ISSN: 1544-9173
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