The lncRNA ZFAS1 regulates lipogenesis in colorectal cancer by binding polyadenylate-binding protein 2 to stabilize SREBP1 mRNA

Huishan Wang; Yuli Chen; Yanwen Liu; Qiuhui Li; Jing Luo; Li Wang; Yuanyuan Chen; Chen Sang; Wen Zhang; Xianxiu Ge; Zhifeng Yao; Lin Miao; Xianghua Liu

doi:10.1016/j.omtn.2021.12.010

The lncRNA ZFAS1 regulates lipogenesis in colorectal cancer by binding polyadenylate-binding protein 2 to stabilize SREBP1 mRNA

Mol Ther Nucleic Acids. 2021 Dec 11:27:363-374. doi: 10.1016/j.omtn.2021.12.010. eCollection 2022 Mar 8.

Authors

Huishan Wang¹, Yuli Chen², Yanwen Liu³, Qiuhui Li², Jing Luo⁴, Li Wang⁵, Yuanyuan Chen², Chen Sang⁶, Wen Zhang³, Xianxiu Ge¹, Zhifeng Yao⁶, Lin Miao⁷, Xianghua Liu²

Affiliations

¹ Department of Gastroenterology, Shanghai Songjiang District Central Hospital, Shanghai 210000, China.
² Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
³ Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210000, China.
⁴ Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210011, China.
⁵ Department of Oncology, The Third Medical School of Nanjing Medical University, Nanjing 210011, China.
⁶ Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow of University, Changzhou G 213003, China.
⁷ Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China.

Abstract

Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality globally. Therefore, a better understanding of the early molecular events of this disease is needed. Long noncoding RNAs (lncRNAs) play a critical role in the regulation of tumorigenesis and cancer progression. In this study, we investigated the characteristics of ZFAS1 in CRC. We analyzed three independent microarray datasets of CRC tissues from GEO and found that ZFAS1 expression was remarkably upregulated in all three datasets. Moreover, we validated the overexpression of ZFAS1 in CRC tissues compared with normal tissues and found that ZFAS1 was positively correlated with tumor size and metastasis in CRC. Knockdown of ZFAS1 significantly suppressed the malignant phenotype and lipogenesis of CRC cells. Mechanistically, ZFAS1 binds polyadenylate-binding protein 2 (PABP2) to stabilize SREBP1 mRNA, thereby increasing the expression of SREBP1 and its target genes stearoyl-CoA desaturase (SCD1) and fatty acid synthase (FASN), thus promoting CRC lipid accumulation. These data demonstrated that ZFAS1 could act as an oncogene for CRC and that ZFAS1 reprograms lipid metabolism by binding with PABP2 to stabilize SREBP1 mRNA accumulation, implicating it as a novel and potent target for the treatment of CRC.

Keywords: CRC; SREBP1; ZFAS1; lipogenesis; lncRNA.