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Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

药学学报:英文版 2023年第6期13卷 2585-2600页

作者： Wenxin Zhang Xiaohui Pan Yanjun Xu Hongjie Guo Mingming Zheng Xi Chen Honghai Wu Fengming Luan qiaojun he Ling Ding Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Medical Thoracic Oncology the Cancer Hospital of University of Chinese Academy of Sciences(Zhejiang Cancer Hospital)Chinese Academy of SciencesHangzhou 310022China Department of Gastrointestinal Surgery Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310009China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China

Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.here,we found that non-small cell lung cancer(NSCLC)patients with higher plasma mevalonate response better to antiPD-(L)1 therapy,as indicated by prolonged progression-free survival and overall survival.Plasma mevalonate levels were positively correlated with programmed death ligand-1(PD-L1)expression in tumor tissues.In NSCLC cell lines and patient-derived cells,supplementation of mevalonate significantly upregulated the expression of PD-L1,whereas deprivation of mevalonate reduced PD-L1 expression.Mevalonate increased CD274 mRNA level but did not affect CD274 transcription.Further,we confirmed that mevalonate improved CD274 mRNA stability.Mevalonate promoted the affinity of the AU-rich elementbinding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA.By in vivo study,we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1,increased the infiltration of CD8^(+)T cells,and improved cytotoxic function of T cells.Collectively,our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody,and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

关键词： Metabolites Mevalonate PD-L1 mRNA stability HuR NSCLC Immune checkpoint blockade

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Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

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Acta Pharmaceutica Sinica B 2021年第2期11卷 309-321页

作者： Yifan Chen Xuejing Shao Ji Cao Hong Zhu Bo Yang qiaojun he Meidan Ying Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Phosphorylation,either of substrates or receptors of CRLs,can alter their interaction.Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases,most often tumorigenesis.These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases,along with the regulation of the stability of specific oncoproteins and tumor suppressors.This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination,and most importantly its influence on tumorigenesis,to provide new directions and strategies for tumor therapy.

关键词： Phosphorylation Cullin-RING ligases Ubiquitination Tumorigenesis Targeted therapy Degradation Crosstalk Kinases

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Yes-associated protein(YAP)and transcriptional coactivator with a PDZ-binding motif(TAZ):a nexus between hypoxia and cancer

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Acta Pharmaceutica Sinica B 2020年第6期10卷 947-960页

作者： Chenxi Zhao Chenming Zeng Song Ye Xiaoyang Dai qiaojun he Bo Yang Hong Zhu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of hepatobiliary and Pancreatic Surgery the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China

Hypoxia is a common feature of solid tumors.As transcription factors,hypoxia-inducible factors(HIFs)are the master regulators of the hypoxic microenvironment;their target genes function in tumorigenesis and tumor development.Intriguingly,both yes-associated protein(YAP)and its paralog transcriptional coactivator with a PDZ-binding motif(TAZ)play fundamental roles in the malignant progression of hypoxic tumors.As downstream effectors of the mammalian Hippo pathway,YAP and/or TAZ(YAP/TAZ)are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2(LATS1/2)-MOB kinase activator 1(MOB 1)complex,which restricts the transcriptional activity of YAP/TAZ.However,dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes,most of which are closely related to cancer.herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia,describe current agents and therapeutic strategies targeting the hypoxia-YAP/TAZ axis,and highlight questions that might have a potential impact in the future.

关键词： YAP TAZ HIFs Hypoxia Solid tumor

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Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

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Acta Pharmaceutica Sinica B 2020年第5期10卷 723-733页

作者： Xi Chen Xiaohui Pan Wenxin Zhang Hongjie Guo Shuyuan Cheng qiaojun he Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Immunotherapy strategies targeting the programmed cell death ligand 1(PD-L1)/programmed cell death 1(PD-1)pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer.However,owing to the heterogeneity of tumors and individual immune systems,PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients.Accumulating evidence has shown that an effective response to anti-PD-Ll/anti-PD-1 therapy requires establishing an integrated immune cycle.Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure.Impairments in the immune cycle can be restored by epigenetic modification,including reprogramming the environment of tumor-associated immunity,eliciting an immune response by increasing the presentation of tumor antigens,and by regulating T cell trafficking and reactivation.Thus,a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

关键词： Epigenetic regulation Immune cycle PD-L1PD-1 blockade Cancer Immunotherapy

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Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2738-2748页

作者： Kailin Li Jieqiong You Qian Wu Wen Meng qiaojun he Bo Yang Chengliang Zhu Ji Cao College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Affiliated Hangzhou First People’s Hospital Zhejiang University School of MedicineHangzhou 310058China Cancer Center of Zhejiang University Hangzhou 310058China

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

关键词： Synthetic lethality Cyclin-dependent kinase Antitumor therapy Oncogenes MYC P53 RAS PARP

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ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1426-1439页

作者： Meng Yuan Xiaobing Chen Yitang Sun Li Jiang Zhongni Xia Kaixiong Ye Hong Jiang Bo Yang Meidan Ying Ji Cao qiaojun he Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 100098China Department of Genetics University of GeorgiaAthensGA 30602USA Tongde Hospital of Zhejiang Province Hangzhou 310012China

The membrane protein claudin-3(CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. here, we report that CLDN3 is positively correlated with ovarian cancer progression both in vitro and in vivo. Of interest, CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3. Moreover, the deprivation of S-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins.Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis. Thus, our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.

关键词： cancer claudin utilizing

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Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

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Acta Pharmaceutica Sinica B 2019年第3期9卷 484-495页

作者： Linlin Chang Yan Hu Yingying Fu Tianyi Zhou Jun You Jiamin Du Lin Zheng Ji Cao Meidan Ying Xiaoyang Dai Dan Su qiaojun he Hong Zhu Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Zhejiang Cancer Hospital Hangzhou310022China

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastaticassociated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly,c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.

关键词： Slug c-Met Drug resistance Ovarian cancer XL184

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Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

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Acta Pharmaceutica Sinica B 2021年第12期11卷 4008-4019页

作者： Meijia Qian Fangjie Yan Weihua Wang Jiamin Du Tao Yuan Ruilin Wu Chenxi Zhao Jiao Wang Jiabin Lu Bo Zhang Nengming Lin Xin Dong Xiaoyang Dai Xiaowu Dong Bo Yang Hong Zhu qiaojun he Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Department of Clinical Pharmacology Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou First People’s HospitalCancer CenterZhejiang University School of MedicineHangzhou 310006China Second Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310009China Cancer Center of Zhejiang University Hangzhou 310058China

Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are reported to be common in CCA patients.However,the underpinning mechanism remains poorly understood.Deubiquitinase(DUB)is regarded as a main orchestrator in maintaining protein homeostasis.here,we identified Josephin domain-containing protein 2(JOSD2)as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner.The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo.Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples.Collectively,this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression,which may provide a potential intervention target for YAP/TAZ-related CCA patients.

关键词： Cholangiocarcinoma Deubiquitinase JOSD2 YAP/TAZ

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Front

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1346-1346页

作者： Ji Cao qiaojun he 不详

Certain post-translational modifications are required for proteins quality control and intracellular transportation. here, Yuan et al. found that S-palmitoylation played an important role in the intracellular transport of CLDN3, a tight junction protein involved in ovarian cancer progression. Mechanistically, ZDHHC12-mediated S-palmitoylation is prerequisite for CLDN3 transporting to the cell membrane.

关键词： al. translational cancer

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Author correction to‘Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA'[Acta Pharmaceutica Sinica B 13(2023)2585-2600]

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Acta Pharmaceutica Sinica B 2023年第10期13卷 4337-4337页

The authors regret that one author was missed in the author list when preparing the manuscript,while the foundation to him was mentioned in the section of Acknowledgments.Dr.Qinjie Weng should be added to the author list because of his contribution in animal study and his foundation help us to complete this study.The authors sincerely apologize for any inconvenience caused to the journal and readers.

关键词： journal correction foundation

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