Rational design of selective HDAC2 inhibitors for liver cancer treatment: computational insights into the selectivity mechanism through molecular dynamics simulations and QM/MM calculations

Yang, Ye; Hu, Baichun; Yang, Yi; Gong, Kaihua; Wang, Huibin; Guo, Qixin; Tang, Xinjie; Li, Yujuan; Wang, Jian

doi:10.1039/d1cp02264d

Cited by 3 publications

(1 citation statement)

References 35 publications

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“…HDAC2 is an epigenetic regulator that controls global gene expression in cells [ 48 ]. Although we showed that HDAC2 inhibitors obtained good results in inhibiting tumor growth in cell and animal experiments, HDAC2 is highly homologous to HDAC8, which might result in unexpected side effects due to the paninhibition of HDAC [ 49 ]. Similar to the results of DNMT inhibitors (e.g., 5-aza-dC) in clinical trials [ 50 ], HDAC paninhibitors approved by the Food and Drug Administration (FDA) might lead to side effects, including cardiac disturbance (arrhythmias), gastric issues (vomiting), or hematologic imbalance (anemia) [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway

et al. 2022

J Exp Clin Cancer Res

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Background Tyrosine kinase inhibitors (TKIs) such as sunitinib are multitarget antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). They are widely used in the treatment of advanced/metastatic renal cancer. However, resistance to TKIs is common in the clinic, particularly after long-term treatment. YTHDC1 is the main nuclear reader protein that binds with m6A to regulate the splicing, export and stability of mRNA. However, the specific role and corresponding mechanism of YTHDC1 in renal cancer cells are still unclear. Methods The Cancer Genome Atlas (TCGA) dataset was used to study the expression of YTHDC1 in ccRCC. Cell counting kit-8 (CCK-8), wound healing, Transwell and xenograft assays were applied to explore the biological function of YTHDC1 in ccRCC. Western blot, quantitative real time PCR (RT‒qPCR), RNA immunoprecipitation PCR (RIP-qPCR), methylated RIP-qPCR (MeRIP-qPCR) and RNA sequencing (RNA-seq) analyses were applied to study the YY1/HDAC2/YTHDC1/ANXA1 axis in renal cancer cells. The CCK-8 assay and xenograft assay were used to study the role of YTHDC1 in determining the sensitivity of ccRCC to sunitinib. Results Our results demonstrated that YTHDC1 is downregulated in ccRCC tissues compared with normal tissues. Low expression of YTHDC1 is associated with a poor prognosis in patients with ccRCC. Subsequently, we showed that YTHDC1 inhibits the progression of renal cancer cells via downregulation of the ANXA1/MAPK pathways. Moreover, we also showed that the YTHDC1/ANXA1 axis modulates the sensitivity of tyrosine kinase inhibitors. We then revealed that HDAC2 inhibitors resensitize ccRCC to tyrosine kinase inhibitors through the YY1/HDAC2 complex. We have identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC. Conclusion We identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.

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Section: Discussionmentioning

confidence: 99%

YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway

et al. 2022

J Exp Clin Cancer Res

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Discovery of a dual-target DYRK2 and HDAC8 inhibitor for the treatment of hepatocellular carcinoma

Zhang,

Guan,

Wang

et al. 2024

Biomedicine & Pharmacotherapy

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Molecular simulations required to target novel and potent inhibitors of cancer invasion

Lu,

Li,

et al. 2023

Expert Opinion on Drug Discovery

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Rational design of selective HDAC2 inhibitors for liver cancer treatment: computational insights into the selectivity mechanism through molecular dynamics simulations and QM/MM calculations

Abstract: The rational design of selective histone deacetylase 2 (HDAC2) inhibitors is beneficial for the therapeutic treatment of liver cancer, though HDAC2 is highly homologous to HDAC8, which may lead to...

Cited by 3 publications

References 35 publications

YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway

YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway

Discovery of a dual-target DYRK2 and HDAC8 inhibitor for the treatment of hepatocellular carcinoma

Molecular simulations required to target novel and potent inhibitors of cancer invasion

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