LncRNA KCNQ1OT1 activated by c-Myc promotes cell proliferation via interacting with FUS to stabilize MAP3K1 in acute promyelocytic leukemia

Doudou Tang,Shangjie Wu,Yafeng Jiang,Yujiao Luo,Hongling Peng,Piao Hu,Guangsen Zhang,Yewei Wang

doi:10.1038/s41419-021-04080-1

Abstract

Uncontrolled proliferation is the hallmark of cancer cells. Previous studies mainly focused on the role of protein-coding genes in cancer cell proliferation. Emerging evidence showed that long non-coding RNAs (lncRNAs) also play critical roles in cancer cell proliferation and growth. LncRNA KCNQ1OT1 is found to contribute to carcinogenesis, but its role in acute promyelocytic leukemia (APL) is unclear. In this study, by analyzing data from Gene Expression Omnibus, The Cancer Genome Atlas database and our clinical samples, we found that KCNQ1OT1 was selectively highly expressed in APL. Functional assays demonstrated that knockdown of KCNQ1OT1 reduced APL cell proliferation and increased apoptosis. Further evidence showed that KCNQ1OT1 was mainly located in the cytoplasm of APL patient-derived NB4 cells and APL patient bone marrow samples. Mechanistically, KCNQ1OT1 bound to RNA binding protein FUS, and silencing either KCNQ1OT1 or FUS reduced the expression level and stability of MAP3K1 mRNA. Whereas KCNQ1OT1 and FUS did not affect each other. Importantly, knockdown of MAP3K1 impaired APL cell proliferation. Finally, c-Myc transactivated KCNQ1OT1 in APL cells through binding to its promoter while knockdown of c-Myc decreased KCNQ1OT1 expression. Our results not only revealed that c-Myc transactivated KCNQ1OT1 and upregulated KCNQ1OT1 promoted APL cell proliferation, but also demonstrated that KCNQ1OT1 bound to FUS to synergistically stabilize MAP3K1 mRNA, thus facilitating APL cell proliferation. This study established a previously unidentified role of KCNQ1OT1 in the development of APL, and KCNQ1OT1 may serve as a potential therapeutic target for APL.

Highlights

Uncontrolled proliferation, which is the outcome of a complex multifactorial process, is the hallmark of cancer cells [1]
KCNQ1OT1 is significantly highly expressed in Acute promyelocytic leukemia (APL) First, we analyzed the expression level of KCNQ1OT1 with GEPIA [23], a web-based tool to compare gene expression based on The Cancer Genome Atlas (TCGA) [24] and Genotype-Tissue Expression (GTEx) data [25]
KCNQ1OT1 has been reported to be involved in lung cancer [13, 15], tongue cancer [35], glioma [16], colorectal cancer [17], bladder cancer [36], prostate cancer [12], and acute myeloid leukemia (AML) [37, 38]

Summary

Introduction

Uncontrolled proliferation, which is the outcome of a complex multifactorial process, is the hallmark of cancer cells [1]. Previous studies mainly focused on the function of protein-coding genes in cancer cell proliferation. Long non-coding RNAs (lncRNAs), which can be transcribed from a considerable fraction of the human genome [2], have been found to play an essential roles in cancer cell proliferation [3]. Identifying functional lncRNAs critical for leukemia cell proliferation and growth will provide comprehensive insights into the pathogenesis of leukemia and new potential targets for leukemia treatment. A full understanding of the pathogenesis of APL will have an important implication for underlying mechanisms and clinical treatments of other subtypes of AML

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