RP11-367G18.1 V2 enhances clear cell renal cell carcinoma progression via induction of epithelial-mesenchymal transition

I-Hung Shao; Pei-Hua Peng; Heng-Hsiung Wu; Ji-Lin Chen; Joseph Chieh-Yu Lai; Jeng-Shou Chang; Han-Tsang Wu; Kou-Juey Wu; See-Tong Pang; Kai-Wen Hsu

doi:10.1002/cam4.5723

RP11-367G18.1 V2 enhances clear cell renal cell carcinoma progression via induction of epithelial-mesenchymal transition

Cancer Med. 2023 Apr;12(8):9788-9801. doi: 10.1002/cam4.5723. Epub 2023 Feb 27.

Authors

I-Hung Shao^{1

2

3

4}, Pei-Hua Peng¹, Heng-Hsiung Wu^{5

6

7}, Ji-Lin Chen⁸, Joseph Chieh-Yu Lai⁹, Jeng-Shou Chang¹, Han-Tsang Wu¹⁰, Kou-Juey Wu^{1

11

12}, See-Tong Pang^{1

2

4}, Kai-Wen Hsu^{5

7

13}

Affiliations

¹ Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
² Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
³ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁵ Research Center for Cancer Biology, China Medical University, Taichung City, Taiwan.
⁶ Program for Cancer Biology and Drug Discovery, China Medical University, Taichung City, Taiwan.
⁷ Drug Development Center, China Medical University, Taichung City, Taiwan.
⁸ Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan.
⁹ Institute of Biomedical Science, China Medical University, Taichung, Taiwan.
¹⁰ Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan.
¹¹ Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
¹² Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
¹³ Institute of Translational Medicine and New Drug Development, China Medical University, Taichung City, Taiwan.

Abstract

Purpose: Metastasis is the end stage of renal cell carcinoma (RCC), and clear cell renal cell carcinoma (ccRCC) is the most common malignant subtype. The hypoxic microenvironment is a common feature in ccRCC and plays an essential role in the regulation of epithelial-mesenchymal transition (EMT). Accumulating evidence manifests that long non-coding RNAs (lncRNAs) participate in RCC tumorigenesis and regulate hypoxia-induced EMT. Here, we identified a lncRNA RP11-367G18.1 induced by hypoxia, that was overexpressed in ccRCC tissues.

Methods: A total of 216 specimens, including 149 ccRCC tumor samples and 67 related normal kidney parenchyma tissue samples, were collected. To investigate the biological fucntions of RP11.367G18.1 in ccRCC, migration, invasion, soft agar colony formation, xenograft tumorigenicity assays, and tail vein and orthotopic metastatic mouse models were performed. The relationship between RP11-367G18.1 and downstream signaling was analyzed utilizing reporter assay, RNA pull-down, chromatin immunopreciptation, and chromatin isolation by RNA purification assays.

Results: Hypoxic conditions and overexpression of HIF-1α increased the level of RP11-367G18.1. RP11-367G18.1 induced EMT and enhanced cell migration and invasion through variant 2. Inhibition of RP11-367G18.1 variant 2 reversed hypoxia-induced EMT phenotypes. An in vivo study revealed that RP11-367G18.1 variant 2 was required for hypoxia-induced tumor growth and metastasis in ccRCC. Mechanistically, RP11-367G18.1 variant 2 interacted with p300 histone acetyltransferase to regulate lysine 16 acetylation on histone 4 (H4K16Ac), thus contributing to hypoxia-regulated gene expression. Clinically, RP11-367G18.1 variant 2 was upregulated in ccRCC tissues, particularly metastatic ccRCC tissues, and it is linked to poor overall survival.

Conclusion: These findings demonstrate the prognostic value and EMT-promoting role of RP11-367G18.1 and indicate that this lncRNA may provide a therapeutic target for ccRCC.

Keywords: H4K16Ac; clear cell renal cell carcinoma; epithelial-mesenchymal transition; hypoxia; lncRNA RP11-367G18.1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma* / genetics
Carcinoma, Renal Cell* / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Chromatin
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Humans
Hypoxia / genetics
Kidney Neoplasms* / pathology
Mice
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Tumor Microenvironment

Substances

RNA, Long Noncoding
Chromatin