MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma
Related Experiment Video
Updated: Jun 27, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Zhihao Wei1, Yuzhong Ye1, Chenchen Liu1
1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Introduction:
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma.
Objectives:
Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance.
Methods:
Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments.
Results:
In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer.
Conclusion:
Our findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.
Insights
Mesoderm induction early response 2 (MIER2) promotes renal cell carcinoma (RCC) malignancy and sunitinib resistance by driving lipid accumulation. Inhibiting the MIER2/HDAC1/P53/PGC1A pathway may overcome drug resistance in RCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Renal cell carcinoma (RCC) is a prevalent urinary system malignancy, with drug resistance significantly impacting advanced cases.
- Abnormal lipid metabolism is increasingly recognized as a driver of tumorigenesis and progression in renal clear cell carcinoma.
Purpose of the Study:
- To elucidate the mechanisms linking aberrant lipid metabolism to drug resistance in RCC.
- To identify novel biomarkers and therapeutic targets for sunitinib-resistant RCC.
Main Methods:
- Bioinformatic analysis to identify key genes.
- Quantitative real-time PCR (qRT-PCR) and Western blot for gene and protein expression.
- Chromatin immunoprecipitation (ChIP) assays to assess protein-DNA interactions.
- Cell line and animal models for functional validation.
Main Results:
- Mesoderm induction early response 2 (MIER2) was identified as a novel RCC biomarker promoting malignancy and sunitinib resistance.
- MIER2 facilitates P53 deacetylation via HDAC1, hindering PGC1A transcription and causing lipid accumulation in RCC.
- Trichostatin A (TSA), an HDAC1 inhibitor, disrupted the MIER2/HDAC1/P53/PGC1A pathway, showing potential in sunitinib-resistant RCC.
Conclusions:
- MIER2 promotes RCC lipid accumulation and drug resistance by deacetylating P53, thereby inhibiting PGC1A expression.
- Lipid-rich RCC cells utilize glycolysis-independent pathways for energy, contributing to targeted drug evasion and resistance.
- Targeting the MIER2/HDAC1/P53/PGC1A axis offers a potential therapeutic strategy for overcoming sunitinib resistance in RCC.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
11:27Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:23Abnormal Proliferation
02:56Treatment Resistant Cancers
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
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,...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...