Huang Hua, Pan Ruining, Zhao Yue, Li Huan, Zhu Huiyu, Wang Sijia, Khan Aamir Ali, Wang Juan, Liu Xinhui
Center of Excellence for Environmental Safety and Biological Effects, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.
Intensive Care Unit, Beijing Tsinghua Changgung Hospital, Beijing 102218, China.
iScience. 2022 Apr 13;25(5):104249. doi: 10.1016/j.isci.2022.104249. eCollection 2022 May 20.
L3MBTL2 is a crucial component of ncPRC1.6 and has been implicated in transcriptional repression and chromatin compaction. However, the repression mechanism of L3MBTL2 and its biological functions are largely undefined. Here, we found that L3MBTL2 plays a distinct oncogenic role in tumor development. We demonstrated that L3MBTL2 repressed downstream CGA through an H2AK119ub1-dependent mechanism. Importantly, the binding of the MGA/MAX heterodimer to the E-box on the CGA promoter enhanced the specific selective repression of CGA by L3MBTL2. CGA encodes the alpha subunit of glycoprotein hormones; however, we showed that CGA plays an individual tumor suppressor role in PDAC. Moreover, CGA-transcript1 (T1) was identified as the major transcript, and the tumor suppression function of CGA-T1 depends on its own glycosylation. Furthermore, glycosylated CGA-T1 inhibited PDAC, partly by repression of autophagy through multiple pathways, including PI3K/Akt/mTOR and TP53INP2 pathways. These findings reveal the important roles of L3MBTL2 and CGA in tumor development.
L3MBTL2是ncPRC1.6的关键组成部分，与转录抑制和染色质浓缩有关。然而，L3MBTL2的抑制机制及其生物学功能在很大程度上尚不清楚。在此，我们发现L3MBTL2在肿瘤发展中发挥独特的致癌作用。我们证明L3MBTL2通过一种依赖H2AK119ub1的机制抑制下游的CGA。重要的是，MGA/MAX异二聚体与CGA启动子上的E盒结合增强了L3MBTL2对CGA的特异性选择性抑制。CGA编码糖蛋白激素的α亚基；然而，我们表明CGA在胰腺癌中发挥个体肿瘤抑制作用。此外，CGA转录本1（T1）被确定为主要转录本，CGA-T1的肿瘤抑制功能取决于其自身的糖基化。此外，糖基化的CGA-T1抑制胰腺癌，部分是通过包括PI3K/Akt/mTOR和TP53INP2途径在内的多种途径抑制自噬。这些发现揭示了L3MBTL2和CGA在肿瘤发展中的重要作用。
