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  3. Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance the production of LOXL2Δ13

Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance the production of LOXL2Δ13

  • J Biol Chem. 2024 May 27;300(7):107414. doi: 10.1016/j.jbc.2024.107414.
Deyuan Pan 1,  Lin Long 1,  Chengyu Li 2,  Yingxin Zhou 2,  Qing Liu 3,  Ziting Zhao 4,  Hui Zhao 2,  Wan Lin 5,  Zhenyuan Zheng 2,  Liu Peng 2,  Enmin Li 6,  Liyan Xu 7
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
  • 2 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
  • 3 State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China.
  • 4 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China.
  • 5 Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
  • 6 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China. Electronic address: nmli@stu.edu.cn.
  • 7 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong Province, China. Electronic address: lyxu@stu.edu.cn.
PMID: 38810697 DOI: 10.1016/j.jbc.2024.107414
Abstract

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion, and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion, and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer exists at the 3' splice site and 5' splice site of LOXL2 exon 13. HnRNPA1 can bind to the exonic splicing silencer and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.

Keywords

LOXL2; LOXL2Δ13; alternative splicing; exon skipping; hnRNPA1.

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