FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.
FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.
复制标题
FOXA1 通过诱导肺腺癌中 IGF2 印记的丧失来防止营养剥夺引起的自噬细胞死亡
DOI：
10.1038/s41419-022-05150-8
复制
发表时间：
2022-08-16
影响因子：
9
通讯作者：
Yi, Mei
中科院分区：
文献类型：
--
作者：
Li, Junjun;Zhang, Yongchang;Wang, Li;Li, Min;Yang, Jianbo;Chen, Pan;Zhu, Jie;Li, Xiayu;Zeng, Zhaoyang;Li, Guiyuan;Xiong, Wei;McCarthy, James B.;Xiang, Bo;Yi, Mei
肺癌仍然是最常见的恶性肿瘤之一，也是全球癌症相关死亡的主要原因。叉头盒蛋白A1(FOXA1)是肺腺癌(LUAD)中扩增的先锋因子。然而，它在LUAD中的作用仍然难以捉摸。在这项研究中，我们发现FOXA1的表达通过抑制自噬细胞死亡(ACD)来提高LUAD细胞在营养缺乏条件下的存活。FOXA1结合胰岛素样生长因子2(IGF2)的印迹控制区，并与DNA甲基转移酶1(DNMT1)相互作用，导致DNMT1介导的IGF2印迹丢失(LOI)和IGF2自分泌。阻断IGF2及其下游的胰岛素样生长因子1受体(IGF1R)可阻断FOXA1对营养缺乏条件下LUAD细胞的保护作用。此外，FOXA1通过IGF2促进溶酶体酶葡萄糖脑苷酶1(GBA1)的泛素化，抑制了ACD的阳性介体--GBA1的表达。值得注意的是，在A549细胞中FOXA1的表达降低了抗血管生成药物inetedanib抑制异种移植瘤生长的效果，而inetedanib与IGF1R抑制剂linsitinib或mTORC1抑制剂雷帕霉素联合使用则增强了肿瘤控制。临床上，在接受贝伐单抗治疗的晚期LUAD患者中，FOXA1蛋白的高表达与不良预后相关。我们的发现揭示了FOXA1在介导IGF2印迹丢失中的先前未知的作用，IGF2通过抑制自噬细胞死亡来增强LUAD细胞抵抗营养缺乏的生存能力。
Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.
登录
查看更多内容
自噬促进炎症微环境下间充质干细胞凋亡。
影响因子：
7.5
作者：
Dang S;Yu ZM;Zhang CY;Zheng J;Li KL;Wu Y;Qian LL;Yang ZY;Li XR;Zhang Y;Wang RX
通讯作者：
Wang RX
RNA结合蛋白YBX1通过与AURKA mRNA结合促进鼻咽癌细胞的细胞增殖和侵袭。
影响因子：
3.9
作者：
Ban Y;Tan Y;Li X;Li X;Zeng Z;Xiong W;Li G;Xiang B;Yi M
通讯作者：
Yi M
天然产物雷公藤甲素通过抑制线粒体己糖激酶-α，诱导头颈癌中 GSDME 介导的细胞焦亡。
DOI：
10.1186/s13046-021-01995-7
发表时间：
2021-06-09
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Cai J;Yi M;Tan Y;Li X;Li G;Zeng Z;Xiong W;Xiang B
通讯作者：
Xiang B
影响因子：
12.4
作者：
Dasari SK;Bialik S;Levin-Zaidman S;Levin-Salomon V;Merrill AH Jr;Futerman AH;Kimchi A
通讯作者：
Kimchi A
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N