Abstract：
Recent studies have highlighted palmitoylation, a novel protein post-translational modification, as a key player in various signaling pathways that contribute to tumorigenesis and drug resistance. Despite this, its role in bladder cancer (BCa) development remains inadequately understood. In this study, ZDHHC9 emerged as a significantly upregulated oncogene in BCa. Functionally, ZDHHC9 knockdown markedly inhibited tumor proliferation, promoted tumor cell apoptosis, and enhanced the efficacy of gemcitabine (GEM) and cisplatin (CDDP). Mechanistically, SP1 was found to transcriptionally activate ZDHHC9 expression. ZDHHC9 subsequently bound to and palmitoylated the Bip protein at cysteine 420 (Cys420), thereby inhibiting the unfolded protein response (UPR). This palmitoylation at Cys420 enhanced Bip\'s protein stability and preserved its localization within the endoplasmic reticulum (ER). ZDHHC9 might become a novel therapeutic target for BCa and could also contribute to combination therapy with GEM and CDDP.
摘要：
最近的研究强调了棕榈酰化，一种新的蛋白质翻译后修饰，作为有助于肿瘤发生和耐药性的各种信号通路的关键参与者。尽管如此,其在膀胱癌（BCa）发展中的作用仍未得到充分理解。在这项研究中,ZDHHC9在BCa中作为显著上调的癌基因出现。功能上,ZDHHC9敲低明显抑制肿瘤增殖，促进肿瘤细胞凋亡，并增强吉西他滨（GEM）和顺铂（CDDP）的疗效。机械上,发现SP1转录激活ZDHHC9表达。ZDHHC9随后在半胱氨酸420（Cys420）处与Bip蛋白结合并棕榈酰化，从而抑制未折叠蛋白反应(UPR)。Cys420的这种棕榈酰化增强了Bip蛋白的稳定性，并保留了其在内质网（ER）中的定位。ZDHHC9可能成为BCa的新型治疗靶标，也可能有助于GEM和CDDP的联合治疗。
