一周快讯：本周表观文献精选（2018.3.31）

L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage

Somaira Nowsheen, Khaled Aziz, Asef Aziz, Min Deng, Bo Qin, Kuntian Luo, Karthik BJeganathan, Henan Zhang, Tongzheng Liu, Jia Yu, Yibin Deng, Jian Yuan, Wei Ding, Jan M van Deursen & Zhenkun Lou

原文链接：

http://www.nature.com/articles/s41556-018-0071-x

原文摘要：

Cells respond to cytotoxic DNA double-strand breaks (DSBs) by recruiting DNA repair proteins to the damaged site. This recruitment is dependent on ubiquitylation of adjacent chromatin areas by E3 ubiquitin ligases such as RNF8 and RNF168, which are recruited sequentially to the DSBs. However, it is unclear what dictates the sequential order and recruits RNF168 to the DNA lesion. Here, we reveal that L3MBTL2 (lethal(3)malignant brain tumour-like protein 2) is the missing link between RNF8 and RNF168. We found that L3MBTL2 is recruited by MDC1 and subsequently ubiquitylated by RNF8. Ubiquitylated L3MBTL2, in turn, facilitates recruitment of RNF168 to the DNA lesion and promotes DNA DSB repair. These results identify L3MBTL2 as a key target of RNF8 following DNA damage and demonstrates how the DNA damage response pathway is orchestrated by ubiquitin signalling.

HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype

Simona Monterisi, Pietro Lo Riso, Karin Russo, Giovanni Bertalot, Manuela Vecchi, Giuseppe Testa, Pier Paolo Di Fiore & Fabrizio Bianchi

原文链接：

http://www.nature.com/articles/s41388-018-0229-9

原文摘要：

HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.

Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+in healthy middle-aged and older adults

Christopher R. Martens ，Blair A. Denman1, Melissa R. Mazzo1, Michael L. Armstrong2, Nichole Reisdorph2, Matthew B. McQueen1, Michel Chonchol3& Douglas R. Seals

原文链接：

http://www.nature.com/articles/s41467-018-03421-7

原文摘要：Nicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+precursors to augment NAD+bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.

Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance

Melissa A. Meyer, John M. Baer, Brett L. Knolhoff, Timothy M. Nywening, Roheena Z. Panni, Xinming Su, Katherine N. Weilbaecher, William G. Hawkins, Cynthia Ma, Ryan C. Fields, David C. Linehan, Grant A. Challen, Roberta Faccio, Rebecca L. Aft  & David G. DeNardo

原文链接：

http://www.nature.com/articles/s41467-018-03600-6

原文摘要：

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141+DCs and mouse CD103+DCs, supports anti-tumor immunity by stimulating CD8+T-cell responses. Here, to understand how cDC1 development changes during tumor progression, we investigated cDC bone marrow progenitors. We found localized breast and pancreatic cancers induce systemic decreases in cDC1s and their progenitors. Mechanistically, tumor-produced granulocyte-stimulating factor downregulates interferon regulatory factor-8 in cDC progenitors, and thus results in reduced cDC1 development. Tumor-induced reductions in cDC1 development impair anti-tumor CD8+T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development.

CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy

Junchao Cai, Rong Li, Xiaonan Xu, Le Zhang, Rong Lian, Lishan Fang, Yongbo Huang, Xianming Feng, Ximeng Liu, Xu Li, Xun Zhu, Heng Zhang, Jueheng Wu, Musheng Zeng, Erwei Song, Yukai He, Yuxin Yin, Jun Li  & Mengfeng Li

原文链接：

http://www.nature.com/articles/s41556-018-0065-8

原文摘要：

The contribution of autophagy to cancer development remains controversial, largely owing to the fact that autophagy can be tumour suppressive or oncogenic in different biological contexts. Here, we show that in non-small-cell lung cancer (NSCLC), casein kinase 1 alpha 1 (CK1α) suppresses tumour growth by functioning as an autophagy inducer to activate an autophagy-regulating, tumour-suppressive PTEN/AKT/FOXO3a/Atg7 axis. Specifically, CK1α bound the C-terminal tail of PTEN and enhanced both PTEN stability and activity by competitively antagonizing NEDD4-1-induced PTEN polyubiquitination and abrogating PTEN phosphorylation, thereby inhibiting AKT activity and activating FOXO3a-induced transcription of Atg7. Notably, blocking CK1α-induced Atg7-dependent autophagy cooperates with oncogenic HRasV12to initiate tumorigenesis of lung epithelial cells. An association of a CK1α-modulated autophagic program with the anti-neoplastic activities of the CK1α/PTEN/FOXO3a/Atg7 axis was demonstrated in xenografted tumour models and human NSCLC specimens. This provides insights into the biological and potentially clinical significance of autophagy in NSCLC.

SNAIL1 action in tumor cells influences macrophage polarization and metastasis in breast cancer through altered GM-CSF

Audrey Brenot, Brett L. Knolhoff, David G. DeNardo & Gregory D. Longmore

原文链接：

http://www.nature.com/articles/s41389-018-0042-x

原文摘要：

The EMT inducer SNAIL1 regulates breast cancer metastasis and its expression in human primary breast tumor predicts for poor outcomes. During tumor progression SNAIL1 has multiple effects in tumor cells that can impact metastasis. An inflammatory tumor microenvironment also impacts metastasis and recently SNAIL1 has been implicated as modulating the secretion of cytokines that can influence the tumor immune infiltrate. Using a spontaneous genetic model of breast cancer metastasis and syngeneic orthotopic transplant experiments we show that the action of SNAIL1 in primary breast tumor cells is required for breast tumor growth and metastasis. It does so, in part, by regulating production of GM-CSF, IL1α, IL-6, and TNFα by breast cancer cells. The SNAIL1-dependent tumor cell secretome modulates the primary tumor-associated macrophage (TAM) polarization. GM-CSF alone modulates TAM polarization and impacts breast cancer metastasis in vivo. This study highlights another role for breast tumor SNAIL1 in cancer progression to metastasis—modulation of the immune microenvironment of primary breast tumors.