Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression
Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression
复制标题
选择性剪接衍生的 intersectin1-L 和 intersectin1-S 在神经胶质瘤进展中发挥相反的功能。
DOI：
10.1038/s41419-019-1668-0
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发表时间：
2019-06-03
影响因子：
9
通讯作者：
Gu, Feng
中科院分区：
文献类型：
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作者：
Shao, Ying;Chong, Wei;Gu, Feng
交叉素1(ITSN1)包含两种异构体：ITSN1-S和ITSN1-L，受选择性剪接的高度调控。然而，选择性剪接的改变及其在癌症中的重要性仍不清楚。在这项研究中，我们对一个大的胶质瘤队列进行的转录组分析表明，这两个异构体在胶质瘤的进展中发挥着相反的功能。我们以前的研究结果表明，ITSN1-S可以促进胶质瘤的发展，但是，ITSN1-L的功能尚不清楚。在本研究中，我们首次证实了ITSN1-L在体内和体外都对胶质瘤的发展起到了抑制作用，这与ITSN1-S的作用相反。此外，我们还阐明了ITSN1-L抑制肿瘤进展的机制。首先，我们发现ITSN1-L可以与α-微管蛋白相互作用，促进依赖HDAC6的α-微管蛋白的脱乙酰化，导致细胞运动能力下降。第二，ITSN1-L可通过FAK/整合素β3途径减弱细胞与基质的黏附。第三，ITSN1-L通过上调N-钙粘附素的表达，并通过ANXA2和TUBB3/TUBB4将N-钙粘附素重新定位到细胞膜上，从而增强细胞与细胞的黏附。综上所述，我们首次发现由选择性剪接产生的两种异构体在胶质瘤的发展中发挥相反的功能。因此，上调ITSN1-L的表达和下调ITSN1-S的表达可能是治疗脑胶质瘤的较好策略。我们的研究为选择性剪接在胶质瘤进展中的重要性奠定了基础，并提出了在选择性剪接水平上完全控制胶质瘤发展成为一种更有效的策略的可能性。
Intersectin1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which is highly regulated by alternative splicing. However, the alteration of alternative splicing and its importance in cancer is still unknown. In this study, our transcriptome analysis by using a large glioma cohort indicated the two isoforms exerted opposite function in glioma progression. Our previous results had shown ITSN1-S could promote glioma development; however, the function of ITSN1-L remained unknown. In this study, we first confirmed that ITSN1-L exerted an inhibitory role in glioma progression both in vivo and in vitro, which was contrary to the function of ITSN1-S. In additional, we also elucidated the mechanisms of ITSN1-L in inhibiting tumor progression. First, we revealed ITSN1-L could interact with alpha-tubulin to promote HDAC6-dependent deacetylation of alpha-tubulin leading to decreased cell motility. Second, ITSN1-L could attenuate cell-substrate adhesion through FAK/integrin beta 3 pathway. Third, ITSN1-L was able to strengthen cell-cell adhesion by upregulating N-cadherin expression and its re-localization to membrane by ANXA2 and TUBB3/TUBB4. In conclusion, we found for the first time that two isoforms produced by alternative splicing exerted opposite functions in glioma development. Therefore, upregulation of ITSN1-L expression as well as downregulation of ITSN1-S expression probably was a better strategy in glioma treatment. Our present study laid a foundation for the importance of alternative splicing in glioma progression and raised the possibility of controlling glioma development completely at an alternative splicing level to be a more effective strategy.