HIF1A-repressed PUS10 regulates NUDC/Cofilin1 dependent renal cell carcinoma migration by promoting the maturation of miR-194-5p

Wenqin Luo; Zhehao Xu; Huan Wang; Zeyi Lu; Lifeng Ding; Ruyue Wang; Haiyun Xie; Qiming Zheng; Yudong Lin; Zhenwei Zhou; Yang Li; Xianjiong Chen; Gonghui Li; Liqun Xia

doi:10.1186/s13578-023-01094-4

HIF1A-repressed PUS10 regulates NUDC/Cofilin1 dependent renal cell carcinoma migration by promoting the maturation of miR-194-5p

Cell Biosci. 2023 Aug 18;13(1):153. doi: 10.1186/s13578-023-01094-4.

Authors

Wenqin Luo^#¹, Zhehao Xu^#¹, Huan Wang¹, Zeyi Lu¹, Lifeng Ding¹, Ruyue Wang¹, Haiyun Xie¹, Qiming Zheng¹, Yudong Lin¹, Zhenwei Zhou¹, Yang Li¹, Xianjiong Chen¹, Gonghui Li², Liqun Xia³

Affiliations

¹ Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
² Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. 3193119@zju.edu.cn.
³ Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. xialiqun@zju.edu.cn.

^# Contributed equally.

Abstract

Background: Renal cell carcinoma (RCC) is characterized by a high rate of distant metastasis, which leads to poor prognosis in patients with advanced RCC. PUS10 has been recognized as a member of the pseudouridine synthase family, and recently other functions beyond the synthesis of the RNA modification have been uncovered. However, little is known about its role in diseases such as cancer.

Methods: RT-qPCR, western blot and immunohistochemistry were used to measure the expression of PUS10 in RCC tissues. Transwell assay, wound healing assay, and in vivo metastasis model were conducted to determine the function of PUS10 in RCC progression. MicroRNA sequencing and GEO database were used to screen for the downstream microRNAs of PUS10. RNA immunoprecipitation, dual luciferase reporter assay, immunostaining, and rescue experiments were employed to establish the PUS10/miR-194-5p/nuclear distribution protein C(NUDC)/Cofilin1 axis in RCC migration. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify its upstream transcriptional regulator.

Results: The expression of PUS10 was significantly decreased in RCC tissues, and low expression predicted poor prognosis. In vitro and in vivo experiments showed that PUS10 suppressed RCC migration, which, however, was independent of its classical pseudouridine catalytic function. Mechanically, PUS10 promoted the maturation of miR-194-5p, which sequentially inhibited RCC migration via disrupting NUDC-dependent cytoskeleton. Furthermore, hypoxia and HIF-1 A were found involved in the downregulation of PUS10.

Conclusion: We unraveled PUS10 restrained RCC migration via the PUS10/miR-194-5p/NUDC/Cofilin1 pathway, which independent of its classical catalytic function. Furthermore, a linkage between the critical tumor microenvironment hallmark with malfunction of the forementioned metastasis inhibition mechanism was presented, as demonstrated by repressed expression of PUS10 due to hypoxia and HIF-1A.

Keywords: HIF-1A; NUDC; PUS10; Renal cell carcinoma; microRNA.

Abstract

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