SIAH1 reverses chemoresistance in epithelial ovarian cancer via ubiquitination of YBX-1

Wujiang Gao,Lu Chen,Shijie Zhao,Taoqiong Li,Xiaolan Zhu,Wenlin Xu,Qi Chen,Mengxue Zhang,Yuefeng Li,Li Lin,Jie Xing,Chunli Sha,Hong Wei,Meiling Yang

doi:10.1038/s41389-022-00387-6

Abstract

Chemoresistance is a severe outcome among patients with epithelial ovarian cancer (EOC) that leads to a poor prognosis. YBX-1 has been shown to cause treatment failure and cancer progression in EOC. However, strategies that directly target YBX-1 are not yet conceivable. Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain. Mechanistic studies show that YBX-1 was ubiquitinated by SIAH1 at lys304 that lead to the instability of its target m5C-modified mRNAs, thus sensitized EOC cells to cDDP. Overexpression of SIAH1 enhanced the antitumor efficacy of cisplatin in vitro and in vivo, which were partially impaired by ectopic expression of YBX-1 or depletion of YBX-1 ubiquitination. In summary, our data identify the SIAH1/YBX-1 interaction as a therapeutic target for overcoming EOC chemoresistance.

Highlights

Epithelial ovarian cancer (EOC) accounts for ~90% of all ovarian cancers which is the most fatal of all gynecological malignancies, mostly diagnosed at advanced stages with poor prognosis [1–4]
It was shown that decreased SIAH1 mRNA existed in part of the human malignant tumors compared with normal tissues, including EOC (Supplementary Fig S1A), and high SIAH1 expression was significantly related to the improvement of progression-free survival (PFS) in EOC patients (Fig. 2A and Supplementary Fig. S1B)
We focused on EOC and found that SIAH1 was remarkably decreased in tumor tissue derived from platinum-resistant (PFS < 6) patients compared with platinum-sensitive (PFS > 6) patients (Fig. 2B and Supplementary Fig. S1C), as well as in EOC patients serum compared with healthy controls (HC) (Fig. 2C)

Summary

Introduction

Epithelial ovarian cancer (EOC) accounts for ~90% of all ovarian cancers which is the most fatal of all gynecological malignancies, mostly diagnosed at advanced stages with poor prognosis [1–4]. As a representative of platinum anticancer drugs, cisplatin (DDP) plays a critical role in the treatment of EOC in clinical chemotherapy [5, 6]. The maintenance of protein homeostasis plays a critical role in many biological processes including tumorigenesis, which is closely related to the post-translational modification of proteins, by covalent attachment of ubiquitin [9–12]. The seven in absentia homologs (SIAHs) comprise a family of highly conserved E3 ubiquitin ligases with a catalytic RING domain, two zinc finger domains, and a substrate-binding domain [11, 22–25]. An increasing number of SIAH1 protein substrates have been authenticated, and they are mainly related to fundamental cellular processes, including hypoxia response pathways (AKAP1, HIPK2, FIH, and PHDs), DNA damage response (TIN2, TRF2, and HIPK2), and cancer inhibition (ACK1, PEG10, DX2, and TRAF4) [28–32]

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