Author: Zhuo, Qifeng ; Yu, Xianjun ; Zhou, Chenjie ; Xu, Xiaowu ; Li, Borui ; Ji, Shunrong ; Li, Zheng ; Fan, Guixiong ; Qin, Yi ; Wang, Jingyi ; Wang, Xiaohong ; Xing, Faliang

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.

01 Aug 2024·Cancer Letters

YBX1 promotes homologous recombination and resistance to platinum-induced stress in ovarian cancer by recognizing m5C modification

Article

Author: Yuan, Lin ; Jiang, Yi ; Wan, Yicong ; Cheng, Wenjun ; Miao, Huixian ; Zhang, Yashuang ; Chen, Tian ; Zhang, Lin ; Meng, Huangyang

Platinum-based chemotherapy causes genetic damage and induces apoptosis in ovarian cancer cells. Enhancing the ability to resist platinum drug-induced DNA damage and apoptotic stress is critical for tumor cells to acquire drug resistance. Here, we found that Y-box binding protein 1 (YBX1) was highly expressed in cisplatin-resistant patient-derived organoids (PDOs) and was a crucial gene for alleviating platinum-induced stress and maintaining drug resistance characteristics in ovarian cancer cells. Mechanistically, YBX1 recognized m5C modifications in CHD3 mRNA and maintained mRNA stability by recruiting PABPC1 protein. This regulatory process enhanced chromatin accessibility and improved the efficiency of homologous recombination (HR) repair, facilitating tumor cells to withstand platinum-induced apoptotic stress. In addition, SU056, an inhibitor of YBX1, exhibited the potential to reverse platinum resistance in subcutaneous and PDO orthotopic xenograft models. In conclusion, YBX1 is critical for ovarian cancer cells to alleviate the platinum-induced stress and may be a potential target for reversing drug-resistant therapies.

19 Jul 2024·ACS Chemical Biology

HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1

Article

Author: Xie, Yan ; Zhou, Xiang ; Liu, Min ; Li, Zhu-Li ; Zhang, Xiao-Lian ; Chen, Hongliang ; Xie, Yuke

Hepatitis C virus (HCV) is a positive-stranded RNA virus that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV RNA genome. However, the roles of the m5C modification and its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, we demonstrate that HCV infection enhances the expression of the host m5C reader YBX1 through the transcription factor MAX. YBX1 acts as an m5C reader, recognizing the m5C-modified NS5A C7525 site in the HCV RNA genome and significantly enhancing HCV RNA stability. This m5C-modification is also required for YBX1 colocalization with lipid droplets and HCV Core protein. Moreover, YBX1 facilitates HCV RNA replication, as well as viral assembly/budding. The tryptophan residue at position 65 (W65) of YBX1 is critical for these functions. Knockout of YBX1 or the application of YBX1 inhibitor SU056 suppresses HCV RNA replication and viral protein translation. To our knowledge, this is the first report demonstrating that the interaction between host m5C reader YBX1 and HCV RNA m5C methylation facilitates viral replication. Therefore, hepatic-YBX1 knockdown holds promise as a potential host-directed strategy for HCV therapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Lung Cancer	Preclinical	US	Oregon Health & Science University	16 Apr 2023

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