p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas

Hsieh, Meng-Hsiung; Choe, Joshua H.; Gadhvi, Jashkaran; Kim, Yoonjung; Arguez, Marcus A.; Palmer, Madison; Gerold, Haleigh; Nowak, Chance M.; Xuan, Hung; Mazambani, Simbarashe; Knighton, Jordan K.; Cha, Matthew; Goodwin, Justin; Kang, Min Kyu; Jeong, Ji Yun; Lee, Shin Yup; Faubert, Brandon; Xuan, Zhenyu; Abel, E. Dale; Scafoglio, Claudio; Shackelford, David B.; Minna, John D.; Singh, Pankaj K.; Shulaev, Vladimir; Bleris, Leonidas; Hoyt, Kenneth; Kim, James; Inoue, Masahiro; DeBerardinis, Ralph J.; Kim, Tae Hoon; Kim, Jung-whan

doi:10.1016/j.celrep.2019.07.027

Cited by 72 publications

(69 citation statements)

References 70 publications

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“…Moreover, the mechanisms driving polarization of mammary epithelial cells in vivo remain elusive and the connection between cell polarity and cell metabolism during mammary gland development, particularly during the high‐energy required stages like puberty and lactation, remains poorly understood. Notably, ∆Np63 regulates the expression of genes involved in metabolism in normal skin homeostasis and squamous cell carcinoma . As we have shown that ∆Np63 is critical for maintenance of tissue homeostasis of the mammary gland , it raises the intriguing possibility that ∆Np63‐dependent effects on high‐energy cellular metabolism during pubertal mammary gland development may contribute to this process.…”

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confidence: 95%

Inducible knockout of ∆Np63 alters cell polarity and metabolism during pubertal mammary gland development

et al. 2019

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The ∆Np63 isoform of the p53‐family transcription factor Trp63 is a key regulator of mammary epithelial stem cells that is involved in breast cancer development. To investigate the role of ∆Np63 at different stages of normal mammary gland development, we generated a ∆Np63‐inducible conditional knockout (cKO) mouse model. We demonstrate that the deletion of ∆Np63 at puberty results in depletion of mammary stem cell‐enriched basal cells, reduces expression of E‐cadherin and β‐catenin, and leads to a closed ductal lumen. RNA‐sequencing analysis reveals reduced expression of oxidative phosphorylation (OXPHOS)‐associated proteins and desmosomal polarity proteins. Functional assays show reduced numbers of mitochondria in the mammary epithelial cells of ΔNp63 cKO compared to wild‐type, supporting the reduced OXPHOS phenotype. These findings identify a novel role for ∆Np63 in cellular metabolism and mammary epithelial cell polarity.

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confidence: 95%

Inducible knockout of ∆Np63 alters cell polarity and metabolism during pubertal mammary gland development

et al. 2019

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“…There is much interest, therefore, in the possibility of synergy with other drugs or other therapies. Hsieh, et al, for example, demonstrated that a squamous cell carcinoma that over expressed GLUT1 receptors showed attenuated growth when animals were on a KD [6]. There was, however, little regression of tumors.…”

Section: Introductionmentioning

confidence: 99%

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

Zou

Fineberg

Pearlman

et al. 2020

Preprint

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14 Background: The effects of diet in cancer, in general, and breast cancer in particular, 15 are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate 16 downstream signaling molecules and are postulated to have therapeutic benefits.17 Obesity and diabetes have been associated with higher incidence of breast cancer.18 Addition of anti-cancer drugs together with diet is also not well studied.19 Methods: Two diets, one ketogenic, the other standard mouse chow, were tested in a 20 spontaneous breast cancer model in mice. The diets were implemented either with or 21 without added rapamycin, an mTOR inhibitor and potential anti-cancer drug.22 Results: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet 23 (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were 24 significantly higher, respectively, than in mice on the standard diet (SD). Growth of 25 primary breast tumors and lung metastases were inhibited, and lifespans were longer in 26 the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in 27 both mouse diet groups, but when combined with the KD was more effective than when 28 combined with the SD.29 Conclusions: The study provides proof of principle that a ketogenic diet a) results in 30 serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) 31 can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of 32 rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect.33 Further, the ketogenic diet in this model produces superior cancer control than standard 34 mouse chow whether with or without added rapamycin. 36 Introduction 37Insulin inhibition by a ketogenic diet has been shown to slow cancer growth and 38 prolong survival in animal models and has shown safety and feasibility in small pilot 39 studies in humans [1], [2] [3] [4] . We previously demonstrated in a pilot study of ten 40 people with diverse, metastatic PET positive cancers that higher levels of ketosis 41 correlated with stability vs. disease progression [5]. The full potential of ketosis in 42 cancer therapy, however, may reside in its potential to synergize with anti-cancer drugs 43 and other modalities of treatment. Increased overall efficacy may permit lower drug 44 doses, thereby reducing their toxicities and side effects. Accordingly, it may be possible 45 that the overall improvement in therapy will result in extended survival with a better 46 quality of life. 47 An understanding of ketogenic diets (KD) in cancer is limited at this point but it 48 seems unlikely that KDs by themselves can control all the features of the oncogenic 49 state. There is much interest, therefore, in the possibility of synergy with other drugs or 50 other therapies. Hsieh, et al., for example, demonstrated that a squamous cell 51 carcinoma that over expressed GLUT1 receptors showed attenuated growth when 52 animals were on a KD [6]. There was, however, little regression of tumors. The addition 53 of th...

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“…Thus, this study indicates that p63 might act as a pioneer factor to establish open chromatin architecture to facilitate access by other lineage-survival factors, such as SOX2, to bind and activate target gene transcription during SCC development. Recently, it has been demonstrated that p63 cooperates with SOX2 to activate intronic enhancer cluster of GLUT1 (SLC2A1), which in turn facilitates GLUT1-mediated glucose influx and generation of NADPH and GSH in SCCs [ 28 ]. The p63 protein also binds to the enhancer region of ZNF185 and promotes its expression in keratinocyte during epithelial differentiation.…”

Section: Tp63 Establishes a Squamous Subtype-specific Enhancer Landscmentioning

confidence: 99%

“…ΔNp63α is the prominent isoform of the TP63 gene expressed in keratinocytes and basal cells of diverse epithelia [ 19 – 21 ] and various SCCs [ 2 ]. ΔNp63α promotes SCC development through regulating different target genes, including cell growth and proliferation [ 22 , 23 ], extracellular matrix (ECM)–receptor interaction [ 24 ], cell adhesion [ 25 – 27 ], glucose metabolism [ 28 , 29 ], anti-oxidant defense [ 30 , 31 ], DNA damage repair [ 32 , 33 ], terminal differentiation [ 34 , 35 ], and inflammation and angiogenesis [ 36 – 41 ] (Fig. 2 ).…”

Section: Introductionmentioning

confidence: 99%

TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development

Man

Tan

Wang

et al. 2020

Cell. Mol. Life Sci.

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Squamous cell carcinoma (SCC) is an aggressive malignancy that can originate from various organs. TP63 is a master regulator that plays an essential role in epidermal differentiation. It is also a lineage-dependent oncogene in SCC. ΔNp63α is the prominent isoform of TP63 expressed in epidermal cells and SCC, and overexpression promotes SCC development through a variety of mechanisms. Recently, ΔNp63α was highlighted to act as an epidermal-specific pioneer factor that binds closed chromatin and enhances chromatin accessibility at epidermal enhancers. ΔNp63α coordinates chromatin-remodeling enzymes to orchestrate the tissue-specific enhancer landscape and three-dimensional high-order architecture of chromatin. Moreover, ΔNp63α establishes squamous-like enhancer landscapes to drive oncogenic target expression during SCC development. Importantly, ΔNp63α acts as an upstream regulator of super enhancers to activate a number of oncogenic transcripts linked to poor prognosis in SCC. Mechanistically, ΔNp63α activates genes transcription through physically interacting with a number of epigenetic modulators to establish enhancers and enhance chromatin accessibility. In contrast, ΔNp63α also represses gene transcription via interacting with repressive epigenetic regulators. ΔNp63α expression is regulated at multiple levels, including transcriptional, post-transcriptional, and post-translational levels. In this review, we summarize recent advances of p63 in epigenomic and transcriptional control, as well as the mechanistic regulation of p63.

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p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas

Cited by 72 publications

References 70 publications

Inducible knockout of ∆Np63 alters cell polarity and metabolism during pubertal mammary gland development

Inducible knockout of ∆Np63 alters cell polarity and metabolism during pubertal mammary gland development

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development

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