2. Academic Validation
  3. LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction

LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction

  • Cancer Lett. 2021 May 28;506:67-82. doi: 10.1016/j.canlet.2021.02.022.
Yawen Ma 1,  Lihua Wang 2,  Fanglin He 3,  Jie Yang 4,  Yi Ding 5,  Shengfang Ge 6,  Xianqun Fan 7,  Yixiong Zhou 8,  Xiaofang Xu 9,  Renbing Jia 10
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: mayawenok@163.com.
  • 2 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: wanglihua0902@126.com.
  • 3 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: hefanglin0925@163.com.
  • 4 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: joeyyang@sjtu.edu.cn.
  • 5 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: dy200921@163.com.
  • 6 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: geshengfang@sjtu.edu.cn.
  • 7 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: fanxq@sjtu.edu.cn.
  • 8 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: zhouyixiong21@gmail.com.
  • 9 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: xuxu0139@hotmail.com.
  • 10 Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: renbingjia@sjtu.edu.cn.
PMID: 33675985 DOI: 10.1016/j.canlet.2021.02.022
Abstract

Very limited progress has been made in the management of advanced melanoma, especially melanoma of uveal origin. Lactamase β (LACTB) is a novel tumor suppressor; however, its biological function in melanoma remains unknown. Herein we demonstrated markedly lower LACTB expression levels in melanoma tissues and cell lines. Overexpression of LACTB suppressed the proliferation, migration and invasion of melanoma cells in vitro. Mechanistically, LACTB inhibited the activity of yes-associated protein (YAP). We showed that the level of phospho-YAP (Serine 127) was increased upon LACTB overexpression, which prevented the translocation of YAP to the nucleus. Further, LACTB could directly bind to PP1A and attenuate the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation and inactivation in a LATS1-independent manner. Additionally, transfection of phosphorylation-defective YAP mutants reversed LACTB-induced tumor suppression. Upstream, we demonstrated that SOX10 binds to the LACTB promoter and negatively regulates its transcription. Overexpression of LACTB also suppressed the tumorigenicity and lung metastasis of MUM2B uveal melanoma cells in vivo. Taken together, our findings indicate a novel SOX10/LACTB/PP1A signaling cascade that renders YAP inactive and modulates melanoma progression, offering a new therapeutic target for melanoma treatment.

Keywords

Catalytic subunit alpha of protein phosphatase-1; Dephosphorylation; Lactamase beta; Melanoma; Yes-associated protein.

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