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

Ji Geng,Rong Zhang,Xinxin Wang,Haidong Xu,Guoqiang Xu,Yan Wang,Zhou Zhu,Zheng-Hong Qin,Xiao Yuan,Junchao Wu,Wenjie Guo

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.

Highlights

Lung cancer is the most common cause of cancer death globally, and nonsmall-cell lung cancer (NSCLC) accounts for the most lung cancer cases[1]
The present work uncovered a novel mechanism of the tumor suppression by damage-regulated autophagy modulator 1 (DRAM1): promoting EGFR endosomal-lysosomal trafficking and degradation in NSCLC in vitro and in vivo through interacting with EPS15 and promoting the assembly of lysosomal vATPase (Fig. 7)
No correlation has been observed between DRAM1 expression and Tp53 mutational status, and DRAM1 expression is partly controlled by the RAS/MAPK pathway in glioblastoma stem cells[26]

Summary

Introduction

Lung cancer is the most common cause of cancer death globally, and nonsmall-cell lung cancer (NSCLC) accounts for the most lung cancer cases[1]. Activated mutations have been identified in multiple oncogenes, including EGFR, ERBB2/3, ALK, KRAS, ROS, MET, AKT, and BRAF in NSCLC2. Aberrant EGFR or EGFRactivating mutations activate various downstream signaling pathways to promote the proliferation, migration, and invasion of NSCLC. Treatment with third-generation EGFR-tyrosine kinase inhibitors (TKIs) has markedly. EGFR T790M and C797S, conferring the inevitable acquired resistance and frequent de novo resistance of NSCLC patients to TKIs4. The mutations of EGFR in NSCLC are concentrated in exons 18–20, encoding the tyrosine kinase domain, and they affect the ATP binding pocket of the tyrosine kinase domain and lead to ligandindependent activation of EGFR. Under a steady state or EGF stimulation, the internalized mutant EGFR travels via the canonical endosome-lysosome route for degradation[5]

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