一周快讯：本周表观文献精选（2018.1.17）

NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming

Qiang Zhuang, Wenjuan Li, Christina Benda, Zhijian Huang, Tanveer Ahmed, Ping Liu, Xiangpeng Guo, David P. Ibañez, Zhiwei Luo, Meng Zhang, Mazid Md. Abdul, Zhongzhou Yang, Jiayin Yang, Yinghua Huang, Hui Zhang, Dehao Huang, Jianguo Zhou, Xiaofen Zhong, Xihua Zhu, Xiuling Fu,Wenxia Fan, Yulin Liu, Yan Xu, Carl Ward, Muhammad Jadoon Khan, Shahzina Kanwal, Bushra Mirza, Micky D. Tortorella, Hung-Fat Tse, Jiayu Chen, Baoming Qin, Xichen Bao, Shaorong Gao,Andrew P. Hutchins & Miguel A. Esteban- Show fewer authors

原文链接：

https://www.nature.com/articles/s41556-018-0047-x

原文摘要：

Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demonstrate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci. Among the Yamanaka factors, recruitment of NCoR/SMRT–HDAC3 to genomic loci is mostly facilitated by c-MYC. Hence, we describe how c-MYC is beneficial for the early phase of reprogramming but deleterious later. Overall, we uncover a role for NCoR/SMRT co-repressors in reprogramming and propose a dual function for c-MYC in this process.

Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage

Paula Gutierrez-Martinez, Leah Hogdal, Manavi Nagai, Miriama Kruta, Rumani Singh, Kristopher Sarosiek, Andre Nussenzweig, Isabel Beerman, Anthony Letai & Derrick J. Rossi

原文链接：

https://www.nature.com/articles/s41556-018-0054-y

原文摘要：

Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous, as ATM signalling and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantated into young recipients. These data indicate that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.

Controlling the master—upstream regulation of the tumor suppressor LKB1

Lars Kullmann & Michael P. Krahn

原文链接：

http://www.nature.com/articles/s41388-018-0145-z

原文摘要：The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer. LKB1 activates several downstream kinases of the AMPK family by direct phosphorylation in the T-loop. In particular the activation of AMPK upon energetic stress has been intensively analyzed in various diseases, including cancer to induce a metabolic switch from anabolism towards catabolism to regulate energy homeostasis and cell survival. In contrast, the regulation of LKB1 itself has long been only poorly understood. Only in the last years, several proteins and posttranslational modifications of LKB1 have been analyzed to control its localization, activity and recognition of substrates. Here, we summarize the current knowledge about the upstream regulation of LKB1, which is important for the understanding of the pathogenesis of many types of tumors.

Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations

Matthew Dankner, April A. N. Rose, Shivshankari Rajkumar, Peter M. Siegel & Ian R. Watson

原文链接：

http://www.nature.com/articles/s41388-018-0171-x

原文摘要：The RAS–RAF–MEK–ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50–80% of BRAF mutations in non-small cell lung cancer and 22–30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient’s tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.

Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice

Jingxiao Wang, Mingjie Dong, Zhong Xu, Xinhua Song, Shanshan Zhang, Yu Qiao, Li Che , John Gordan, Kaiwen Hu, Yan Liu, Diego F. Calvisi& Xin Chen

原文链接：

http://www.nature.com/articles/s41388-018-0188-1

原文摘要：

Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1flox/flox, and Notch2flox/floxmice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice.

LRH1 enhances cell resistance to chemotherapy by transcriptionally activating MDC1 expression and attenuating DNA damage in human breast cancer

S. Wang Z. Zou, X. Luo, Y. Mi, H. Chang& D. Xing

原文链接：

www.nature.com/articles/s41388-018-0193-4#auth-4

原文摘要：

Liver receptor homolog-1 (LRH1) has been shown to promote tumor proliferation and development. However, the functions of LRH1 in mediating cancer cells chemoresistance are still not clear. Here, we found LRH1 levels were significantly elevated in primary breast cancer tissues in patients who developed early recurrence. Similarly, adriamycin (ADR)-resistant breast cancer cell lines also exerted high LRH1 expression. Indeed, overexpression of LRH1 attenuated cytotoxicity of chemotherapeutic drugs ADR and cisplatin (DDP) in breast cancer cells in vitro and in nude mice tumor model. Comet and BrdU assays showed overexpression of LRH1 blocked breast cancer cells DNA damage by chemotherapeutic drug, whereas depletion of LRH1 enhanced DNA damage. Remarkably, knockdown of LRH1 decreased the levels and foci of DNA damage marker γH2AX induced by ADR and DDP. Furthermore, plasmid end-joining assay indicated that knockdown of LRH1 significantly decreased non-homologous end-joining (NHEJ)-mediated double-strand break (DSB) repair efficiencies. Afterwards, we provided evidences that LRH1 promoted MDC1 transcription by directly activating MDC1 promoter and therefore increased γH2AX levels. Importantly, a LRH1-binding site mapped between −1812 and −1804 bp of the proximal MDC1 promoter was identified. Moreover, LRH1 and MDC1 mRNA levels were positively correlated in recurrent breast cancer samples. These results implied LRH1 enhanced breast cancer cell chemoresistance by upregulating MDC1 and attenuating DNA damage. Additionally, we elucidated the coactivator NCOA3 acted synergistically with LRH1 to promote MDC1 expression and chemoresistance. Altogether, LRH1-MDC1 signaling might be considered as a novel molecular target for designing novel therapeutic regimen in chemotherapy resistance breast cancer.