Xingang Li1, Hongming Lu2, Guilian Fan2, Miao He2, Yu Sun2, Kai Xu2, Fengjun Shi3. 1. Department of Orthopaedics, Heilongjiang General Hospital of Daqing Oil Field, Daqing, 163000, China. 2. Department of Pathology, Heilongjiang General Hospital of Daqing Oil Field, Daqing, 163000, China. 3. Department of Orthopaedics, Heilongjiang General Hospital of Daqing Oil Field, Daqing, 163000, China. fengjun_shi_dq@163.com.
Abstract
PURPOSE: Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive. METHOD: Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS. RESULTS: We found that HOTAIR is highly expressed in OS cells and the knockdown of HOTAIR leads to the down-regulation of DNMT1, as well as the decrease of global DNA methylation level. RNA-sequencing analysis of HOTAIR-regulated gene shows that CDKN2A is significantly repressed by HOTAIR. A series of experiments show that HOTAIR represses the expression of CDKN2A through inhibiting the promoter activity of CDKN2A by DNA hypermethylation. Further evidence shows that HOTAIR activates the expression of DNMT1 through repressing miR-126, which is the negative regulator of DNMT1. Functionally, HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDKN2A axis. CONCLUSION: These results not only enrich our understanding of the regulation relationship between non-coding RNA, DNA methylation, and gene expression, however, also provide a novel direction in developing more sophisticated therapeutic strategies for OS patients.
PURPOSE:Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive. METHOD: Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS. RESULTS: We found that HOTAIR is highly expressed in OS cells and the knockdown of HOTAIR leads to the down-regulation of DNMT1, as well as the decrease of global DNA methylation level. RNA-sequencing analysis of HOTAIR-regulated gene shows that CDKN2A is significantly repressed by HOTAIR. A series of experiments show that HOTAIR represses the expression of CDKN2A through inhibiting the promoter activity of CDKN2A by DNA hypermethylation. Further evidence shows that HOTAIR activates the expression of DNMT1 through repressing miR-126, which is the negative regulator of DNMT1. Functionally, HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDKN2A axis. CONCLUSION: These results not only enrich our understanding of the regulation relationship between non-coding RNA, DNA methylation, and gene expression, however, also provide a novel direction in developing more sophisticated therapeutic strategies for OS patients.
Entities:
Keywords:
CDKN2A; DNA methylation; HOTAIR; Osteosarcoma; Proliferation
Authors: Maija R J Kohonen-Corish; Jason Tseung; Charles Chan; Nicola Currey; Owen F Dent; Stephen Clarke; Les Bokey; Pierre H Chapuis Journal: Int J Cancer Date: 2013-12-06 Impact factor: 7.396
Authors: Su Jeong Lee; Hyo-Sung Jeon; Jin-Sung Jang; Sun Ha Park; Ga Young Lee; Byung-Heon Lee; Chang Ho Kim; Young Mo Kang; Won Kee Lee; Sin Kam; Rang Woon Park; In-San Kim; Young Lae Cho; Tae Hoon Jung; Jae Yong Park Journal: Carcinogenesis Date: 2004-11-04 Impact factor: 4.944
Authors: Timothy J Ley; Li Ding; Matthew J Walter; Michael D McLellan; Tamara Lamprecht; David E Larson; Cyriac Kandoth; Jacqueline E Payton; Jack Baty; John Welch; Christopher C Harris; Cheryl F Lichti; R Reid Townsend; Robert S Fulton; David J Dooling; Daniel C Koboldt; Heather Schmidt; Qunyuan Zhang; John R Osborne; Ling Lin; Michelle O'Laughlin; Joshua F McMichael; Kim D Delehaunty; Sean D McGrath; Lucinda A Fulton; Vincent J Magrini; Tammi L Vickery; Jasreet Hundal; Lisa L Cook; Joshua J Conyers; Gary W Swift; Jerry P Reed; Patricia A Alldredge; Todd Wylie; Jason Walker; Joelle Kalicki; Mark A Watson; Sharon Heath; William D Shannon; Nobish Varghese; Rakesh Nagarajan; Peter Westervelt; Michael H Tomasson; Daniel C Link; Timothy A Graubert; John F DiPersio; Elaine R Mardis; Richard K Wilson Journal: N Engl J Med Date: 2010-11-10 Impact factor: 91.245
Authors: Jordan Ayers; Rowan J Milner; Galaxia Cortés-Hinojosa; Alberto Riva; Sandra Bechtel; Bikash Sahay; Matthew Cascio; Amandine Lejeune; Keijiro Shiomitsu; Carlos Souza; Oscar Hernandez; Marc Salute Journal: J Vet Diagn Invest Date: 2021-01-15 Impact factor: 1.279
Authors: Yang Zhao; Zhimeng Wang; Qian Wang; Liang Sun; Ming Li; Cheng Ren; Hanzhong Xue; Zhong Li; Kun Zhang; Dingjun Hao; Na Yang; Zhe Song; Teng Ma; Yao Lu Journal: Cancer Cell Int Date: 2020-03-30 Impact factor: 5.722