AI Article Synopsis
- The study investigates the role of CHD1L in renal cell carcinoma (RCC), revealing that its overexpression is linked to increased cancer aggressiveness and poorer patient outcomes, as well as contributing to resistance against the drug sunitinib.
- Through various laboratory techniques, researchers found that CHD1L interacts with SIRT7, which helps stabilize CHD1L and enhances hypoxia signaling pathways, ultimately promoting tumor growth and metastasis in RCC.
- Targeting CHD1L with a specific inhibitor was shown to enhance the effectiveness of sunitinib, suggesting potential therapeutic strategies for overcoming drug resistance in RCC.
Article Abstract
Background: Aberrant interplay between epigenetic reprogramming and hypoxia signaling contributes to renal cell carcinoma progression and drug resistance, which is an essential hallmark. How the chromatin remodelers enhance RCC malignancy remains to be poorly understood. We aimed to elucidate the roles of CHD1L in determining hypoxia signaling activation and sunitinib resistance.
Methods: The qRT-PCR, western blotting, and immunohistochemistry technologies were used to detect CHD1L expressions. Lentivirus transfection was used to generate stable CHD1L-KD cells. The roles of SIRT7/CHD1L were evaluated by CCK-8, wound healing, transwell assays, xenograft models, and tail-vein metastasis models. Co-immunoprecipitation, Chromatin Immunoprecipitation (ChIP), and luciferase reporter assays were conducted to explore epigenetic regulations.
Results: We screened and validated that CHD1L is up-regulated in RCC and correlates with poorer prognosis of patients. CHD1L overexpression notably enhances cell proliferation, migration, and self-renewal capacities in vitro and in vivo. Mechanistically, SIRT7 physically interacts with CHDL1 and mediates the deacetylation of CHD1L. Wild-type SIRT7, but not H187Y dead mutant, stabilizes CHD1L protein levels via attenuating its ubiquitination levels. SIRT7 is increased in RCC and correlates with hazardous RCC clinical characteristics. SIRT7 depends on CHD1L to exert its tumor-promoting functions. Accumulated CHD1L amplifies HIF-2α-driven transcriptional programs via interacting with HIF-2α. CHD1L recruits BRD4 and increases the RNA polymerase II S2P loading. CHD1L ablation notably abolishes HIF-2α binding and subsequent transcriptional activation. CHD1L overexpression mediates the sunitinib resistance via sustaining VEGFA and targeting CHD1L reverses this effect. Specific CHD1L inhibitor (CHD1Li) shows a synergistic effect with sunitinib and strengthens its pharmaceutical effect.
Conclusions: These results uncover a CHD1L-mediated epigenetic mechanism of HIF-2α activation and downstream sunitinib resistance. The SIRT7-CHD1L-HIF-2α axis is highlighted to predict RCC prognosis and endows potential targets.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10493023 | PMC |
| http://dx.doi.org/10.1186/s13578-023-01113-4 | DOI Listing |
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