The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.
Ting-Yu Chang, Yan Yan, Zih-Yao Yu, Moeez Rathore, Nian-Zhe Lee, Hui-Ju Tseng, Li-Hsin Cheng, Wei-Jan Huang, Wei Zhang, Ernest R. Chan, Yulan Qing, Ming-Lun Kang, Rui Wang, Kelvin K. Tsai, John J. Pink, William E. Harte, Stanton L. Gerson, Sung-Bau Lee
BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-mutant mCRC improved clinical benefits; unfortunately, inevitable acquired resistance limits the treatment outcome, and the mechanism has not been validated. Here, we discovered that monoacylglycerol O-Acyltransferase 3 (MOGAT3) mediated diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib/cetuximab by dissecting BRAFV600E-mutant mCRC patient-derived xenograft (PDX) model exposed to encorafenib/cetuximab administration. Mechanistically, upregulated MOGAT3 promotes DAG synthesis and reduces fatty acid oxidation (FAO)-promoting DAG accumulation and activating PKCα-CRAF-MEK-ERK, driving acquired resistance. Resistance-induced hypoxia promotes MOGAT3 transcriptional elevation; simultaneously, MOGAT3-mediated DAG accumulation increases HIF1A expression in translation level through PKCα-CRAF-eIF4E activation, strengthening the resistance status. Intriguingly, reducing intratumoral DAG by fenofibrate or Pf-06471553 restores the antitumor efficacy of encorafenib/cetuximab on resistant BRAFV600E-mutant mCRC, interrupted PKCα-CRAF-MEK-ERK signaling. These findings reveal the critical metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate may prove beneficial for resistant BRAFV600E-mutant mCRC patients.
Jiawei Wang, Huogang Wang, Wei Zhou, Xin Luo, Huijuan Wang, Qing Meng, Jiaxin Chen, Xiaoyu Chen, Yinqiang Liu, David W. Chan, Zhenyu Ju, Zhangfa Song
Lorenza Bellusci, Hana Golding, Surender Khurana
The sensory cells that transduce the signals for hearing and balance are highly specialized mechanoreceptors called hair cells that reside in the sensory epithelia of the inner ear. Loss of hair cells from toxin exposure and age can cause balance disorders and is essentially irreversible due to the inability of mammalian vestibular organs to regenerate physiologically active hair cells. Here, we show substantial regeneration of hair cells in a mouse model of vestibular damage by treatment with a combination of glycogen synthase kinase 3β and histone deacetylase inhibitors. The drugs stimulated supporting cell proliferation and differentiation into hair cells. The new hair cells were reinnervated by vestibular afferent neurons, rescuing otolith function by restoring head translation-evoked otolith afferent responses and vestibuloocular reflexes. Drugs that regenerate hair cells thus represent a potential therapeutic approach to the treatment of balance disorders.
Hanae Lahlou, Hong Zhu, Wu Zhou, Albert S.B. Edge
Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhanced the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD showed potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be stimulated for therapy to remove traumatic memory trace.
Ze-Jie Lin, Xue Gu, Wan-Kun Gong, Mo Wang, Yan-Jiao Wu, Qi Wang, Xin-Rong Wu, Xin-Yu Zhao, Michael X. Zhu, Lu-Yang Wang, Quanying Liu, Ti-Fei Yuan, Wei-Guang Li, Tian-Le Xu
T cell–based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.
Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H. Wood, Devina D. Lakhiani, Abate A. Bashaw, Lisa M. Nilsson, Ji Li, Edward R. Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair R.R. Forrest, Suraj Sakaram, Rafael Carretero, Günter J. Hämmerling, Jonas A. Nilsson, Gabriel Y.F. Lee, Ruth Ganss
Multiple Sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons’ myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to auto-antigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14+ monocytes, mature dendritic cells (mDCs) and Vitamin-D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HD). Using multi-omics, we identified a switch in these cell types towards proinflammatory features characterized by alterations in the AhR and NF-kB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared to those from HD, which were fully restored through direct AhR agonism and using in vivo or in vitro Dimethyl Fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis (EAE) mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS.
Federico Fondelli, Jana Willemyns, Roger Domenech-Garcia, Maria José Mansilla, Gerard Godoy-Tena, Anna G. Ferreté-Bonastre, Alex Agúndez-Moreno, Silvia Presas-Rodriguez, Cristina Ramo-Tello, Esteban Ballestar, Eva Martínez-Cáceres
Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC–mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.
Guochao Wu, Shuya Liu, Julia Hagenstein, Malik Alawi, Felicitas E. Hengel, Melanie Schaper, Nuray Akyüz, Zhouning Liao, Nicola Wanner, Nicola M. Tomas, Antonio Virgilio Failla, Judith Dierlamm, Jakob Körbelin, Shun Lu, Tobias B. Huber
Strategies beyond hormone-related therapy should need to be developed to improve prostate cancer mortalityfor better disease management. Here we show that FUBP1 and its methylation are essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppresses the development of prostate cancer. FUBP1 accelerated prostate cancer development across in various pre-clinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence shorter treatment durations in our patient cohort. Suppressed prostate cancer progression was observed in different various genetic mouse models expressing FUBP1 mutants deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, successfully disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in different various pre-clinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potentially therapeutic strategy for disease prostate cancer management.
Weiwei Yan, Xun Liu, Xuefeng Qiu, Xuebin Zhang, Jiahui Chen, Kai Xiao, Ping Wu, Chao Peng, Xiaolin Hu, Zengming Wang, Jun Qin, Liming Sun, Luonan Chen, Denglong Wu, Shengsong Huang, Lichen Yin, Zhenfei Li
Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essentially meaningful. Here, we identified an under-appreciated Serine/Threonine kinase, CDKL3 (Cyclin-dependent kinase like 3), crucially drives the rapid cell cycle progression and cell growth in cancers. Mechanism-wise, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate Retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of CDK4 by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 (Cyclin-dependent kinase 4/6) inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes the acquired resistance of the latter. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presented an integrated paradigm of cancer cell cycle regulation and suggested CDKL3-targeting as a feasible approach in cancer treatment.
Haijiao Zhang, Jiahui Lin, Shaoqin Zheng, Lanjing Ma, Zhongqiu Pang, Hongyi Yin, Chengcheng Meng, Yinuo Wang, Qing Han, Xi Zhang, Zexu Li, Liu Cao, Lijun Liu, Teng Fei, Daming Gao, Liang Yang, Xueqiang Peng, Chen Ding, Shixue Wang, Ren Sheng
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