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// Hong Zhou 1, 2, 5, * , Jiawei Zhang 2, 3, * , Ying Gu 1, 2, 3, * , Xiaoxian Gan 3, 4 , Yichao Gan 1, 2 , Weiwei Zheng 1, 2 , Byung-Wook Kim 3 , Xiaohua Xu 1 , Xiaoya Lu 1, 2 , Qi Dong 2 , Shu Zheng 2 , Wendong Huang 3 , Rongzhen Xu 1, 2 1 Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China 2 Cancer Institute of Zhejiang University, Hangzhou 310009, China 3 Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA 4 Zhejiang Academy of Medical Sciences, Hangzhou 310012, China 5 Hangzhou First People’s Hospital, Hangzhou 310006, China * These authors contributed equally to this work. Correspondence to: Rongzhen Xu, e-mail: zrxyk10@zju.edu.cn Wendong Huang, e-mail: whuang@coh.org Keywords: cancer cell, RNA giant nuclear body, nuclear RNA trafficking Received: August 25, 2015 Accepted: November 25, 2015 Published: December 15, 2015 ABSTRACT Constitutive synthesis of oncogenic mRNAs is essential for maintaining the uncontrolled growth of cancer cells. However, little is known about how these mRNAs are exported from the nucleus to the cytoplasm. Here, we report the identification of a RNA giant nuclear body (RNA-GNB) that is abundant in cancer cells but rare in normal cells. The RNA-GNB contains a RNA core surrounded by a protein shell. We identify 782 proteins from cancer-associated RNA-GNBs, 40% of which are involved in the nuclear mRNA trafficking. RNA-GNB is required for cell proliferation, and its abundance is positively associated with tumor burden and outcome of therapies. Our findings suggest that the RNA-GNB is a novel nuclear RNA trafficking organelle that may contribute to the nuclear mRNA exporting and proliferation of cancer cells.

As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.

Highly tumorigenic stem-like cells, considered tumor-initiating cells (TICs), are the main cause of lung cancer initiation, relapse, and drug resistance. In this study, we identified that Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ) was aberrantly expressed in highly tumorigenic stem-like lung cancer cells, and was also correlated with poor prognosis in human lung cancer. Functionally, CaMKIIγ enhanced stem-like traits and the tumorigenicity of lung cancer cells in an Akt- and β-catenin-dependent manner. In addition, we found that CaMKIIγ upregulated Oct4 expression via Akt-mediated histone acetylation. Taken together, our findings reveal a critical role of CaMKIIγ in regulating the stemness and tumorigenicity of lung cancer cells and offer a promising therapeutic target for TICs.