2. Academic Validation
  3. FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation

FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation

  • Cell Death Dis. 2024 Jan 12;15(1):37. doi: 10.1038/s41419-024-06425-y.
Kai Chen # 1,  Yue Wang # 1,  Xingna Dai 1,  Jingjing Luo 1,  Shangshang Hu 1,  Zhihui Zhou 2,  Jinglong Shi 2,  Xueshan Pan 3,  Tong Cao 4,  Jun Xia 3,  Yuyun Li 5,  Zhiwei Wang 6,  Jia Ma 7
Affiliations

Affiliations

  • 1 Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Anhui, Bengbu, 233030, China.
  • 2 Department of Laboratory Medicine, School of Laboratory Medicine, Bengbu Medical University, Anhui, Bengbu, 233030, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Anhui, Bengbu, 233030, China.
  • 4 Department of Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui, Bengbu, 233004, China.
  • 5 Department of Clinical Laboratory Diagnostics, School of Laboratory Medicine, Bengbu Medical University, Anhui, Bengbu, 233030, China.
  • 6 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Anhui, Bengbu, 233030, China. zhiweichina@126.com.
  • 7 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Anhui, Bengbu, 233030, China. majiamj10@126.com.
  • # Contributed equally.
PMID: 38216561 DOI: 10.1038/s41419-024-06425-y
Abstract

FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in Cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3-FBXO31-SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.

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