2. Academic Validation
  3. DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

  • Cell Death Dis. 2020 Sep 17;11(9):768. doi: 10.1038/s41419-020-02979-9.
Ji Geng 1 2,  Rong Zhang 1,  Xiao Yuan 3,  Haidong Xu 1,  Zhou Zhu 4,  Xinxin Wang 1,  Yan Wang 1,  Guoqiang Xu 1,  Wenjie Guo 5,  Junchao Wu 6,  Zheng-Hong Qin 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 2 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Pathology Department, The First Affiliated Hospital of Soochow University, Suzhou, 215123, PR China.
  • 4 Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210093, PR China.
  • 6 Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. chaochaow@163.com.
  • 7 Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. qinzhenhong@suda.edu.cn.
PMID: 32943616 DOI: 10.1038/s41419-020-02979-9
Abstract

Lung Cancer is the leading cause of cancer-associated mortality worldwide. DNA damage-regulated Autophagy modulator 1 (DRAM1) plays an important roles in Autophagy and tumor progression. However, the mechanisms by which DRAM1 inhibits tumor growth are not fully understood. Here, we report that DRAM1 was decreased in nonsmall-cell lung carcinoma (NSCLC) and was associated with poor prognosis. We confirmed that DRAM1 inhibited the growth, migration, and invasion of NSCLC cells in vitro. Furthermore, overexpression of DRAM1 suppressed xenografted NSCLC tumors in vivo. DRAM1 increased EGFR endocytosis and lysosomal degradation, downregulating EGFR signaling pathway. On one side, DRAM1 interacted with EPS15 to promote EGFR endocytosis, as evidence by the results of proximity labeling followed by proteomics; on the other, DRAM1 recruited V-ATP6V1 subunit to lysosomes, thereby increasing the assemble of the V-ATPase complex, resulting in decreased lysosomal pH and increased activation of lysosomal proteases. These two actions of DRAM1 results in acceleration of EGFR degradation. In summary, these in vitro and in vivo studies uncover a novel mechanism through which DRAM1 suppresses oncogenic properties of NSCLC by regulating EGFR trafficking and degradation and highlights the potential value of DRAM1 as a prognostic biomarker in lung cancers.

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