Ser ⁷⁸⁴ phosphorylation: a clinically relevant enhancer of VCP function in the DNA damage response

Abstract

Valosin-containing protein (VCP) is essential for proteostasis during many cellular processes. However, it remains uncertain how its diverse functions are selectively regulated. We recently showed that DNA damage-induced Ser 784 phosphorylation specifically increases VCP function for the DNA damage response and significantly influences the survival of chemotherapy-treated breast cancer patients.

Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor

“…First, our cell line and patient data suggested that pSer 784 -VCP instead of total VCP levels predict PDAC response to genotoxic chemotherapies. This is conceptually consistent with the pleiotropic effects of VCP on global proteostasis [13][14][15]54] and the specific activating effect of Ser 784 phosphorylation on DDR function of VCP [25,26]. As with our prior study using surgical breast tumor samples [25], the PDAC TMA used in this study was constructed using tumor samples collected at surgery before adjuvant chemotherapies given to nearly all patients.…”

“…VCP is phosphorylated at Ser 784 in its C-terminal tail by the PIKK kinases (ATM/ATR/DNA-PK) in response to different genotoxic insults [22][23][24]. However, the functional importance of Ser 784 phosphorylation remained unknown until our recent study [25,26]. Using an isogenic knockdown and rescue approach, we demonstrated that Ser 784 phosphorylation of VCP is essential for chromatin-associated protein degradation, DNA repair, checkpoint signaling, and cellular survival in response to diverse genotoxic chemotherapeutic treatments.…”

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

“…From a clinical perspective, the authors associated nuclear pSer784-VCP levels with poor outcomes for patients with triple-negative breast cancer receiving chemotherapy but not with other types of therapy, suggesting that pSer784-VCP might be a potential predictive biomarker for the efficacy of chemotherapy [ 79 ]. Subsequently, the same authors maintained that low levels of pSer784-VCP should be considered a predictive biomarker for patients with breast cancer who are treated with genotoxic therapies and that patients with higher levels of pSer784-VCP might benefit from chemosensitization DDR kinase family inhibitors already in clinical use [ 80 ].…”

“…Thus, VCP/p97 represents a potential prognostic biomarker and a therapeutic target. [71] Gastric cancer greater tumor size, presence of vascular and lymphatic invasion, lymph node metastasis, and shorter overall and disease free survival [72] cell survival, degradation of cellular regulators, and gastric carcinogenesis [73,74] low levels of CHOP and DR5 [75] Esophageal cancer higher frequencies of lymph node metastasis, deeper invasion, metastasis, and shorter disease free and overall survival [76] shorter overall survival [77] Breast cancer shorter overall survival [78] poor outcomes of triple-negative patients receiving chemotherapy [79,80] Hematological cancer tumor grade, stage, histological subtype, recurrence and shorter overall and disease-free survival of patients with B-cell lymphoma [104] multiple myeloma development and progression [105] poor prednisone responders in pediatric patients with acute lymphoblastic leukemia [106] exosome generation and secretion in Jurkat tumor cells [107] Melanoma advanced radiotherapy [108] immune escape [109] Glioblastoma radiosensitivity of glioblastoma cells, and survival time of xenografted mice with radiation treatment [110,111] HDAC6 levels and temozolomide resistance therapy [112] Ovarian cancer chemotherapy response in patients receiving the platinum-taxane combination [113] Testicular cancer development of different types of human testicular tumors [114] Bladder cancer shorter survival following bladder removal by cystectomy [115] Squamous cell carcinoma development of squamous cell carcinoma [116] 3.1. VCP/p97 in Gastrointestinal Cancers 3.1.1.…”

Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

“…Mutations at codon 470 and 616 in the D1-D2 linker region that are associated with ATPase hyperactivity are resistant to VCP inhibitors [ 139 ]. Phosphorylation of C-terminal serine 784 activates the VCP DNA damage response [ 140 , 141 , 142 , 143 ]. The recruitment of VCP to double stranded DNA breaks relies on the VCP cofactors UFD1-NPL4 [ 144 ].…”