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

Abstract

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.

The regulation of N6‐methyladenosine modification in PD‐L1‐induced anti‐tumor immunity

“…So, HNRNPC was reported to be correlated with recurrence and served as an independent risk factor along with YTHDF2 in pancreatic neuroendocrine neoplasms. 85 Generally, the Reader expressed in the cell nucleus, such as YTHDC1 and HNRNPC, maintain the stability of m6A-modified mRNA and subsequently promote mRNA nuclear exportation, 86,87 suggesting the up-regulation of PD-L1 expression. Readers in the cytoplasm, by comparison, have a disparate function in m6A-modified mRNA expression.…”

“…Generally, the Reader expressed in the cell nucleus, such as YTHDC1 and HNRNPC, maintain the stability of m6A‐modified mRNA and subsequently promote mRNA nuclear exportation, 86,87 suggesting the up‐regulation of PD‐L1 expression. Readers in the cytoplasm, by comparison, have a disparate function in m6A‐modified mRNA expression.…”

Biological and pharmacological roles of m6A modifications in cancer drug resistance

“…In treating glioblastoma multiforme (GBM) with temozolomide, METTL3 increased the m6A modification of histone modify-related gene transcripts leading to the development of chemoresistance [ 124 ]. In ccRCC, YTHDC1 acted as an m 6 A reader and regulated the sensitivity of tyrosine kinase inhibitors (TKI) such as sunitinib through the YTHDC1/ANXA1 axis [ 125 ]. In conclusion, research on the molecular mechanisms of m 6 A in different chemotherapeutic agents has attracted increasing attention, offering new prospects and potential therapeutic targets for reversing therapeutic resistance (Fig.…”

“…In treating glioblastoma multiforme (GBM) with temozolomide, METTL3 increased the m6A modification of histone modify-related gene transcripts leading to the development of chemoresistance [124]. In ccRCC, YTHDC1 acted as an m 6 A reader and regulated the sensitivity of tyrosine kinase inhibitors (TKI) such as sunitinib through the YTHDC1/ANXA1 axis [125].…”

HDAC2 as a target for developing anti-cancer drugs

“…C-MYC was shown to directly increase the expression of HDAC2 by binding to the promoter sequences of HDAC2 [8] . Yin yang 1 (YY1) bound to HDAC2 and regulated the sensitivity of clear cell renal cell carcinoma (ccRCC) to tyrosine kinase inhibitors in ccRCC [9] . Given that HDAC2 can regulate the expression of various genes, HDAC2 might contribute to the pathogenesis of various diseases.…”