2. Academic Validation
  3. ALKBH5 suppresses tumor progression via an m6A-dependent epigenetic silencing of pre-miR-181b-1/YAP signaling axis in osteosarcoma

ALKBH5 suppresses tumor progression via an m6A-dependent epigenetic silencing of pre-miR-181b-1/YAP signaling axis in osteosarcoma

  • Cell Death Dis. 2021 Jan 11;12(1):60. doi: 10.1038/s41419-020-03315-x.
Ye Yuan 1 2 3 4,  Gege Yan 1,  Mingyu He 1,  Hong Lei 1,  Linqiang Li 5,  Yang Wang 2 3,  Xiaoqi He 1,  Guanghui Li 1,  Quan Wang 1,  Yuelin Gao 1,  Zhezhe Qu 1,  Zhongting Mei 1,  Zhihua Shen 2 3,  Jiaying Pu 2 3,  Ao Wang 2 3,  Wei Zhao 1 2,  Huiwei Jiang 1 2,  Weijie Du 6,  Lei Yang 7
Affiliations

Affiliations

  • 1 Department of Orthopedics at The First Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, 150086, Harbin, China.
  • 2 Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China.
  • 3 Department of Clinical pharmacology, College of Pharmacy, Harbin Medical University, 150086, Harbin, China.
  • 4 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, China.
  • 5 Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.
  • 6 Department of Orthopedics at The First Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, 150086, Harbin, China. adugo@163.com.
  • 7 Department of Orthopedics at The First Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, 150086, Harbin, China. yangray83@vip.qq.com.
PMID: 33431791 DOI: 10.1038/s41419-020-03315-x
Abstract

ALKBH5 is the main Enzyme for m6A-based demethylation of RNAs and it has been implicated in many biological and pathophysiological processes. Here, we aimed to explore the potential involvement of ALKBH5 in osteosarcoma and decipher the underlying cellular/molecular mechanisms. We discovered downregulated levels of demethylase ALKBH5 were correlated with increased m6A methylation in osteosarcoma cells/tissues compared with normal osteoblasts cells/tissues. ALKBH5 overexpression significantly suppressed osteosarcoma cell growth, migration, invasion, and trigged cell Apoptosis. In contrast, inhibition of ALKBH5 produced the opposite effects. Whereas ALKBH5 silence enhanced m6A methylations of pre-miR-181b-1 and YAP-mRNA exerting oncogenic functions in osteosarcoma. Moreover, upregulation of YAP or downregulation of mature miR-181b-5p displayed a remarkable attenuation of anti-tumor activities caused by ALKBH5. Further results revealed that m6A methylated pre-miR-181b-1 was subsequently recognized by m6A-binding protein YTHDF2 to mediate RNA degradation. However, methylated YAP transcripts were recognized by YTHDF1 to promote its translation. Therefore, ALKBH5-based m6A demethylation suppressed osteosarcoma Cancer progression through m6A-based direct/indirect regulation of YAP. Thus, ALKBH5 overexpression might be considered a new approach of replacement therapy for osteosarcoma treatment.

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