长期使用酪氨酸激酶抑制剂(TKIs)后的耐药性已成为延长透明细胞肾细胞癌(ccRCC)患者生存时间的障碍。这里,应用基于CRISPR的全基因组筛选,揭示HDAC8参与降低ccRCC细胞对舒尼替尼的敏感性.机械上,HDAC8在K245位点脱乙酰ETS1,促进ETS1与HIF-2α的相互作用,增强ETS1/HIF-2α复合物的转录活性。然而,抑制HDAC8对致敏TKI的抗肿瘤作用不是很理想。随后,HDAC8的抑制增加了NEK1的表达,并在T241位点上调NEK1磷酸化ETS1,以通过在ETS1-K245位点的乙酰化阻碍促进ETS1和HIF-2α之间的相互作用。此外,还发现TKI处理通过抑制ccRCC细胞中STAT3磷酸化来增加HDAC8的表达。这两个发现强调了ccRCC中对TKIs和HDAC8抑制剂的获得性抗性的潜在机制。最后,合成了HDAC8-in-PROTACs,通过降解HDAC8并克服ccRCC对TKIs的抗性来优化HDAC8抑制剂的作用。总的来说,结果显示HDAC8是ccRCC靶向治疗耐药的潜在候选药物.
Drug resistance after long-term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome-wide CRISPR-based screening to reveal that
HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically,
HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF-2α and enhance the transcriptional activity of the ETS1/HIF-2α complex. However, the antitumor effect of inhibiting
HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up-regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF-2α by impeded acetylation at ETS1-K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and
HDAC8 inhibitors in ccRCC. Finally,
HDAC8-in-PROTACs to optimize the effects of
HDAC8 inhibitors through degrading
HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC-targeted therapies.