HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells

Song, Kwon Ho; Choi, Chel Hun; Lee, Hyo‐Jung; Oh, Se Jin; Woo, Seon Rang; Hong, Soon Oh; Noh, Kyung Hee; Cho, Hanbyoul; Chung, Eun Joo; Kim, Jae Hoon; Chung, Joon Yong; Hewitt, Stephen M.; Baek, Seungin; Lee, Kyung Mi; Yee, Cassian; Son, Moeun; Mao, Chih Ping; Wu, T. C.; Kim, Tae Woo

doi:10.1158/0008-5472.can-17-0072

Cited by 71 publications

(81 citation statements)

References 43 publications

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“…We next investigated the factor mediating histone deacetylation at the Atp5h and ATP5H loci during immune editing. Recently, we discovered that upregulation of HDAC1 is important for epigenetic reprogramming and acquisition of both stem-like properties and resistance to CTLs by CaSki P3 cells (27). Consistently, we observed HDAC1 upregulation upon in vivo immune editing of TC-1 tumor cells (Supplemental Figure 4).…”

Section: Resultssupporting

confidence: 82%

“…We discovered that immune editing alters the epigenetic landscape of tumor cells via histone deacetylase 1 (HDAC1) upregulation (27), which turns off ATP5H expression via promoter deacetylation. The epigenetic loss of ATP5H facilitates cancer immune escape and multimodal resistance to immunotherapy, chemotherapy, and radiotherapy.…”

Section: Resultsmentioning

confidence: 99%

“…Primary antibodies against phosphorylated AKT (p-AKT) (no. (27). Indeed, knockdown of Hdac1 or HDAC1 in TC-1 and CaSki tumor cells after immune editing led to an increase in ATP5H levels ( Figure 1, G and H), a reduction of ROS, and a decrease in HIF-1α protein expression and VEGF secretion by tumor cells (Supplemental Figure 14).…”

Section: Cells the Production And Maintenance Of Hpv-16 E7mentioning

confidence: 89%

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Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Song¹,

Kim²,

Lee³

et al. 2018

Journal of Clinical Investigation

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The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1α stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Cells the Production And Maintenance Of Hpv-16 E7mentioning

confidence: 89%

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Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Song¹,

Kim²,

Lee³

et al. 2018

Journal of Clinical Investigation

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“…As the crucial role of Nanog in stemness maintenance of embryonic stem cell and cancer stem cell has been well established and extensively studied by other groups (Song et al, 2017; Jin et al, 2016; Noh et al, 2012; Chambers et al, 2003; Mitsui et al, 2003), we intend to further pinpoint whether SPOP deficiency upregulates prostate CSC properties in a Nanog-dependent manner. To this end, we examined the effects of SPOP deficiency in the presence or absence of Nanog on various prostate CSC traits.…”

Section: Resultsmentioning

confidence: 99%

SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression

et al. 2019

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SUMMARY Frequent SPOP mutation defines the molecular feature underlying one of seven sub-types of human prostate cancer (PrCa). However, it remains largely elusive how SPOP functions as a tumor suppressor in PrCa. Here, we report that SPOP suppresses stem cell traits of both embryonic stem cells and PrCa cells through promoting Nanog poly-ubiquitination and subsequent degradation. Mechanistically, Nanog, but not other pluripotency-determining factors including Oct4, Sox2, and Klf4, specifically interacts with SPOP via a conservative degron motif. Importantly, cancer-derived mutations in SPOP or at the Nanog-degron (S68Y) disrupt SPOP-mediated destruction of Nanog, leading to elevated cancer stem cell traits and PrCa progression. Notably, we identify the Pin1 oncoprotein as an upstream Nanog regulator that impairs its recognition by SPOP and thereby stabilizes Nanog. Thus, Pin1 inhibitors promote SPOP-mediated destruction of Nanog, which provides the molecular insight and rationale to use Pin1 inhibitor(s) for targeted therapies of PrCa patients with wild-type SPOP.

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“…For instance, Song et al . (32) found that NANOG‐mediated up‐regulation of antiapoptotic myeloid cell leukemia 1 protein leads to immune resistance and chemo resistance. Dhillon et al .…”

Section: Discussionmentioning

confidence: 99%

EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell‐like properties

Chu

Feng

et al. 2019

FASEB j.

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Trastuzumab is a successful, rationally designed therapy that provides significant clinical benefit for human epidermal growth factor receptor‐2 (HER2)‐positive breast cancer patients. However, about half of individuals with HER2‐positive breast cancer do not respond to trastuzumab treatment because of various resistance mechanisms, including but not limited to: 1) shedding of the HER2 extracellular domain, 2) steric hindrance (e.g., MUC4 and MUC1), 3) parallel pathway activation (this is the general mechanism cited in the quote above), 4) perturbation of downstream signaling events (e.g., PTEN loss or PIK3CA mutation), and 5) immunologic mechanisms (such as FcR polymorphisms). EPHA5, a receptor tyrosine kinase, has been demonstrated to act as an anticancer agent in several cancer cell types. In this study, deletion of EPHA5 can significantly increase the resistance of HER2‐positive breast cancer patients to trastuzumab. To investigate how EPHA5 deficiency induces trastuzumab resistance, clustered regularly interspaced short palindromic repeat technology was used to create EPHA5‐deficient variants of breast cancer cells. EPHA5 deficiency effectively increases breast cancer stem cell (BCSC)‐like properties, including NANOG, CD133+, E‐cadherin expression, and the CD44+/CD24−/low phenotype, concomitantly enhancing mammosphere‐forming ability. EPHA5 deficiency also caused significant aggrandized tumor malignancy in trastuzumab‐sensitive xenografts, coinciding with the up‐regulation of BCSC‐related markers and intracellular Notch1 and PTEN/AKT signaling pathway activation. These findings highlight that EPHA5 is a potential prognostic marker for the activity of Notch1 and better sensitivity to trastuzumab in HER2‐positive breast cancer. Moreover, patients with HER2‐positive breast cancers expressing high Notch1 activation and low EPHA5 expression could be the best candidates for anti‐Notch1 therapy.—Li, Y., Chu, J., Feng, W., Yang, M., Zhang, Y., Zhang, Y., Qin, Y., Xu, J., Li, J., Vasilatos, S. N., Fu, Z., Huang, Y., Yin, Y. EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell–like properties. FASEB J. 33, 4851–4865 (2019). http://www.fasebj.org

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HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells

Cited by 71 publications

References 43 publications

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression

EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell‐like properties

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