YTHDC1 受 YY1/HDAC2 复合物下调，并通过靶向 ANXA1-MAPK 通路控制 ccRCC 对舒尼替尼的敏感性。
YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway.
机构信息
Department of Urology, The Second Xiangya Hospital, Central South University, 410011, Changsha, Hunan, China.
Uro-Oncology Institute of Central South University, 410011, Changsha, Hunan, China.
出版信息
J Exp Clin Cancer Res. 2022 Aug 17;41(1):250. doi: 10.1186/s13046-022-02460-9.
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 mA 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.
背景
酪氨酸激酶抑制剂（TKI）如舒尼替尼是透明细胞肾细胞癌（ccRCC）的多靶点抗血管生成药物。它们广泛用于治疗晚期/转移性肾细胞癌。然而，临床上对 TKI 的耐药性很常见，尤其是在长期治疗后。YTHDC1 是与 mA 结合以调节 mRNA 的剪接、输出和稳定性的主要核读蛋白。然而，YTHDC1 在肾癌细胞中的具体作用和相应机制尚不清楚。
方法
使用癌症基因组图谱（TCGA）数据集研究 YTHDC1 在 ccRCC 中的表达。细胞计数试剂盒-8（CCK-8）、划痕愈合、Transwell 和异种移植实验用于探索 YTHDC1 在 ccRCC 中的生物学功能。Western blot、定量实时 PCR（RT-qPCR）、RNA 免疫沉淀 PCR（RIP-qPCR）、甲基化 RIP-qPCR（MeRIP-qPCR）和 RNA 测序（RNA-seq）分析用于研究肾癌细胞中的 YY1/HDAC2/YTHDC1/ANXA1 轴。CCK-8 测定和异种移植实验用于研究 YTHDC1 在确定 ccRCC 对舒尼替尼敏感性中的作用。
结果
我们的结果表明，与正常组织相比，YTHDC1 在 ccRCC 组织中下调。YTHDC1 的低表达与 ccRCC 患者的预后不良相关。随后，我们表明 YTHDC1 通过下调 ANXA1/MAPK 通路抑制肾癌细胞的进展。此外，我们还表明 YTHDC1/ANXA1 轴调节酪氨酸激酶抑制剂的敏感性。然后，我们揭示了 HDAC2 抑制剂通过 YY1/HDAC2 复合物使 ccRCC 对酪氨酸激酶抑制剂重新敏感。我们已经确定了一个新的 YY1/HDAC2/YTHDC1/ANXA1 轴，调节 ccRCC 的进展和化疗敏感性。
结论
我们确定了一个新的 YY1/HDAC2/YTHDC1/ANXA1 轴，调节 ccRCC 的进展和化疗敏感性。
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