2. Academic Validation
  3. A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression

A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression

  • BMC Biol. 2021 Sep 7;19(1):192. doi: 10.1186/s12915-021-01112-2.
Tao Shen  # 1 2 3,  Wangxiao Xia  # 4,  Sainan Min  # 5,  Zixuan Yang  # 1 2 3,  Lehua Cheng  # 4,  Wei Wang 1 2 3,  Qianxi Zhan 1 2 3,  Fanghong Shao 1 2 3,  Xuehan Zhang 1 2 3,  Zhiyu Wang 6,  Yan Zhang 7,  Guodong Shen 1 2,  Huafeng Zhang 3,  Li-Ling Wu 8,  Guang-Yan Yu 5,  Qing-Peng Kong 9 10 11,  Xiangting Wang 12 13 14
Affiliations

Affiliations

  • 1 Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, China.
  • 3 Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
  • 4 State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, 650223, China.
  • 5 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
  • 6 Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, 071000, China.
  • 7 School of Health Services Management, Anhui Medical University, Hefei, 230032, Anhui, China.
  • 8 Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
  • 9 State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, 650223, China. [email protected].
  • 10 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. [email protected].
  • 11 KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China. [email protected].
  • 12 Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 13 Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, China. [email protected].
  • 14 Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 34493285 DOI: 10.1186/s12915-021-01112-2
Abstract

Background: Long noncoding RNAs (lncRNAs) are important regulators in tumor progression. However, their biological functions and underlying mechanisms in hypoxia adaptation remain largely unclear.

Results: Here, we established a correlation between a Chr3q29-derived lncRNA gene and tongue squamous carcinoma (TSCC) by genome-wide analyses. Using RACE, we determined that two novel variants of this lncRNA gene are generated in TSCC, namely LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). RNA-sequencing in 887S or 887L loss-of-function cells identified their common downstream target as Carbonic Anhydrase IX (CA9), a gene known to be upregulated by hypoxia during tumor progression. Mechanistically, our results showed that the hypoxia-augmented 887S and constitutively expressed 887L functioned in opposite directions on tumor progression through the common target CA9. Upon normoxia, 887S and 887L interacted. Upon hypoxia, the two variants were separated. Each RNA recognized and bound to their responsive DNA cis-acting elements on CA9 promoter: 887L activated CA9's transcription through recruiting HIF1α, while 887S suppressed CA9 through DNMT1-mediated DNA methylation.

Conclusions: We provided hypoxia-permitted functions of two antagonistic lncRNA variants to fine control the hypoxia adaptation through CA9.

Keywords

Alternative promoter; Alternative splicing; Cancer; Carbonic anhydrase 9; DNA methylation; Hypoxia; Hypoxia-induced factor; Long noncoding RNA.

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