Open AccessTargeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation
Author(s) -
Zhang HuiLu,
Chen Ping,
Yan HeXin,
Fu GongBo,
Luo FeiFei,
Zhang Jun,
Zhao ShiMin,
Zhai Bo,
Yu JiangHong,
Chen Lin,
Cui HaoShu,
Chen Jian,
Huang Shuai,
Zeng Jun,
Xu Wei,
Wang HongYang,
Liu Jie
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202103887
Subject(s) - glutamine , cancer research , biology , cancer cell , cancer stem cell , stem cell , liver cancer , cancer , microbiology and biotechnology , biochemistry , hepatocellular carcinoma , genetics , amino acid
Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient‐derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem‐like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non‐TICs into stem‐like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem‐like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3‐mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2‐HDAC3‐GS axis decrease TICs and promote xenografts regression upon glutamine‐starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2‐HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine‐starvation therapy and limit the rapid growth and malignant progression of tumors.