TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling

  • Nat Cell Biol. 2018 Dec;20(12):1421-1433. doi: 10.1038/s41556-018-0219-8.
Youn-Sang Jung  1 ,  Sohee Jun  1 ,  Moon Jong Kim  1 ,  Sung Ho Lee  1 ,  Han Na Suh  1 ,  Esther M Lien  1 ,  Hae-Yun Jung  1 ,  Sunhye Lee  1 ,  Jie Zhang  1 ,  Jung-In Yang  1 ,  Hong Ji  2 ,  Ji Yuan Wu  3 ,  Wenqi Wang  4 ,  Rachel K Miller  2  5  6  7 ,  Junjie Chen  1  6  7 ,  Pierre D McCrea  2  6  7 ,  Scott Kopetz  3 ,  Jae-Il Park  8  9  10
Affiliations
  • 1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
  • 5. Department of Pediatrics, The University of Texas McGovern Medical School, Houston, TX, USA.
  • 6. Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, TX, USA.
  • 7. Program in Genes and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 9. Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 10. Program in Genes and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
PMID: 30374053 DOI: 10.1038/s41556-018-0219-8
Abstract

Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to Cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal Cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar Proton Pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signalling in colorectal Cancer. Genetic ablation of TMEM9 inhibits colorectal Cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/β-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal Cancer treatment.