Downregulation of lncRNA APCDD1L-AS1 due to DNA hypermethylation and loss of VHL protein expression promotes the progression of clear cell renal cell carcinoma

Wuping Yang^1,2,3*, Jingcheng Zhou^1,2,3*, Zedan Zhang^1,2,3, Kenan Zhang^1,2,3, Yawei Xu^1,2,3, Lei Li^1,2,3, Lin Cai^1,2,3, Yanqing Gong^1,2,3✉, Kan Gong^1,2,3✉

1. Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.
2. Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.
3. Institute of Urology, Peking University, Beijing 100034, P.R. China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Citation:
Yang W, Zhou J, Zhang Z, Zhang K, Xu Y, Li L, Cai L, Gong Y, Gong K. Downregulation of lncRNA APCDD1L-AS1 due to DNA hypermethylation and loss of VHL protein expression promotes the progression of clear cell renal cell carcinoma. Int J Biol Sci 2022; 18(6):2583-2596. doi:10.7150/ijbs.71519. Available from https://www.ijbs.com/v18p2583.htm

Abstract

Background: The current studies only indicated that long non-coding RNA (lncRNA) APCDD1L-AS1, as a novel lncRNA, may play a role in oral squamous cell carcinoma and lung cancer. However, its potential role in clear cell renal cell carcinoma (ccRCC) and its possible mechanism of action remain vague.

Methods: TCGA-KIRC and GEO data and qRT-PCR and pyrosequencing results of clinical specimens were used to identify the expression level and DNA methylation status of APCDD1L-AS1. The effects of APCDD1L-AS1 overexpression on ccRCC growth and metastasis were determined by function experiments. Western blot and Tandem mass tags (TMT) were utilized to explore the relationship between APCDD1L-AS1 and VHL expression and its downstream underlying mechanisms.

Results: The expression of APCDD1L-AS1 was downregulated in ccRCC. Decreased APCDD1L-AS1 expression was related to higher tumor stage and histological grade and shorter RFS (Relapse-free survival). Besides, APCDD1L-AS1 overexpression restrained the growth and metastasis of ccRCC cells in vitro and in vivo. Moreover, reduced APCDD1L-AS1 expression could be caused by DNA hypermethylation and loss of von Hippel Lindau (VHL) protein expression. Furthermore, the dysregulation of histones expression caused by APCDD1L-AS1 overexpression may be one of the important mechanisms to suppress the progression of ccRCC.

Conclusion: APCDD1L-AS1 was able to inhibit the progression of ccRCC, and its decreased expression could be caused by DNA hypermethylation and loss of VHL protein expression. Therefore, APCDD1L-AS1 may serve as a new therapeutic target in the treatment of ccRCC.

Keywords: long non-coding RNA, APCDD1L-AS1, clear cell renal cell carcinoma, DNA hypermethylation, von Hippel Lindau