L3MBTL2-mediated CGA transcriptional suppression promotes pancreatic cancer progression through modulating autophagy

Hua Huang; Ruining Pan; Yue Zhao; Huan Li; Huiyu Zhu; Sijia Wang; Aamir Ali Khan; Juan Wang; Xinhui Liu

doi:10.1016/j.isci.2022.104249

L3MBTL2-mediated CGA transcriptional suppression promotes pancreatic cancer progression through modulating autophagy

iScience. 2022 Apr 13;25(5):104249. doi: 10.1016/j.isci.2022.104249. eCollection 2022 May 20.

Authors

Hua Huang¹, Ruining Pan¹, Yue Zhao², Huan Li¹, Huiyu Zhu³, Sijia Wang¹, Aamir Ali Khan¹, Juan Wang¹, Xinhui Liu¹

Affiliations

¹ 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.
² Intensive Care Unit, Beijing Tsinghua Changgung Hospital, Beijing 102218, China.
³ School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology.