SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.
SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.
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SPT6招募SND1共同激活人端粒酶逆转录酶促进结肠癌进展
DOI：
10.1002/1878-0261.12878
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发表时间：
2021-04
影响因子：
6.6
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Diao C;Guo P;Yang W;Sun Y;Liao Y;Yan Y;Zhao A;Cai X;Hao J;Hu S;Yu W;Chen M;Wang R;Li W;Zuo Y;Pan J;Hua C;Lu X;Fan W;Zheng Z;Deng W;Luo G;Guo W
结直肠癌（Colorectal cancer， CRC）在年轻成人患者中的发病率持续上升，需要对结直肠癌发病机制进行更深入的研究和认识，并开发新的诊断和治疗策略。我们的研究表明，SPT6与葡萄球菌核酸酶和Tudor结构域1 （SND1）协同作用，通过靶向人类端粒酶逆转录酶（hTERT）促进结直肠癌的进展，并提出抑制SPT6 - SND1 - hTERT轴可能在结直肠癌中产生治疗易感。人类端粒酶逆转录酶（hTERT）在包括结直肠癌（CRC）在内的癌症的发生和发展中起着极其重要的作用。然而，hTERT在不同癌症类型中的上游调控机制仍然知之甚少。在此，我们揭示了CRC中hTERT的候选转录因子，并探讨了其在调节hTERT表达和CRC存活中的作用及其相应的分子机制，旨在开发基于机制的联合靶向治疗。利用拉下/质谱分析发现了hTERT启动子上可能的结合蛋白。在人CRC细胞系和小鼠模型中评估SPT6对hTERT表达和CRC存活的调控。在上述两个水平上也进行了机制研究，重点研究了SPT6与葡萄球菌核酸酶和Tudor结构域1 （SND1）在控制hTERT表达和CRC进展中的协同作用。研究SPT6、SND1、hTERT在小鼠模型及原位结直肠癌患者肿瘤组织中的表达相关性及临床意义。SPT6被确定为可能与hTERT启动子结合的转录因子。SPT6敲低可降低hTERT启动子活性，下调hTERT蛋白表达水平，抑制细胞增殖、侵袭和干细胞样特性，促进细胞凋亡诱导，增强体外化疗药物敏感性。SPT6沉默也导致携带人类来源结肠癌细胞异种移植物的小鼠肿瘤生长和转移延迟。在机制上，SND1与SPT6相互作用，共同控制hTERT表达和CRC细胞的增殖、干性和生长。无论是小鼠模型还是原位结直肠癌患者，SPT6、SND1、hTERT在结直肠癌组织中均同时高表达，且三者之间的两两表达均呈显著正相关。总之，我们的研究表明SPT6与SND1协同作用通过靶向hTERT促进CRC的发展，并提出抑制SPT6 - SND1 - hTERT轴可能在CRC中产生治疗易损性。
Colorectal cancer (CRC) is continuously rising among young adult patients, necessitating more forethoughtful study and understanding of the mechanisms behind CRC and the development of the new diagnostic and therapeutic strategies. Our research demonstrated that SPT6 synergized with staphylococcal nuclease and Tudor domain containing 1 (SND1) to promote CRC progression by targeting human telomerase reverse transcriptase (hTERT) and put forward that inhibiting SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC. Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism‐based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull‐down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem‐like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human‐derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co‐control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC.
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影响因子：
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