E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer
Ke Li1, Xufen Zheng1, Hua Tang2
1Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health-Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non-small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell-specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry-based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.
Insights
The gene MKRN3, linked to central precocious puberty (CPP), acts as a tumor suppressor. It inhibits non-small cell lung cancer (NSCLC) growth by regulating protein synthesis via PABPC1.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Central precocious puberty (CPP) is associated with germline mutations in the MKRN3 gene.
- Epidemiological studies suggest a link between CPP and cancer development.
- MKRN3 mutations are found in non-small cell lung cancers (NSCLCs).
Purpose of the Study:
- To investigate the role of the MKRN3 gene in cancer, particularly NSCLC.
- To elucidate the mechanism by which MKRN3 influences tumor growth and proliferation.
- To determine if MKRN3 functions as a tumor suppressor.
Main Methods:
- Analysis of MKRN3 mutations and expression in NSCLC patient cohorts.
- In vitro and in vivo experiments reconstituting MKRN3 in NSCLC cells.
- Generation and analysis of MKRN3 knockout mouse models for lung cancer susceptibility.
- Proteomic screening to identify MKRN3 substrates, followed by ubiquitination assays.
Main Results:
- Genomic MKRN3 aberrations are enriched in NSCLC with KRAS mutations.
- Low MKRN3 expression correlates with poor patient survival.
- Restoring MKRN3 inhibits NSCLC cell growth in vitro and in vivo.
- MKRN3 deficiency accelerates urethane-induced lung cancer in mice.
- MKRN3 ubiquitinates PABPC1, impacting protein synthesis and cell proliferation.
Conclusions:
- The CPP-associated gene MKRN3 functions as a tumor suppressor in NSCLC.
- MKRN3's tumor suppressor activity relies on its E3 ligase function and PABPC1 ubiquitination.
- Dysregulation of MKRN3 contributes to NSCLC development and progression.
Related Concept Videos
02:23Abnormal Proliferation
01:23Negative Regulator Molecules
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:38Mitogens and the Cell Cycle