Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer

作者：Rashmi Bharti, Goutam Dey, Debjit Khan, Alex Myers, Olivia G. Huffman, Caner Saygin, Chad Braley, Elliott G. Richards, Naseer Sangwan, Belinda Willard, Justin D. Lathia, Paul L. Fox, Feng Lin, Babal K. Jha, J. Mark Brown, Jennifer S. Yu, Mohammed Dwidar, Amy Joehlin‐Price, Roberto Vargas, Chad M. Michener, Michelle S. Longworth, Ofer Reizes · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-02028-5 · 被引用次数：22 · 研究领域：Complement system in diseases、Angiogenesis and VEGF in Cancer、Erythrocyte Function and Pathophysiology

BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers. METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing. RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, st...