SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Tian Gao, Xiaohong Zhang, Jing Zhao, Feng Zhou, Yaya Wang, Zheng Zhao, Jinliang Xing, Biliang Chen, Jibin Li, Shujuan Liu Abstract Salt-inducible kinase 2 (SIK2), which belongs to the AMP-activated protein kinase family, modulates various biological functions including fatty acid oxidation. However, the role of SIK2 in glucose metabolism reprogramming remains unclear in ovarian cancer (OC) cells. Here, we found that SIK2 significantly enhanced the Warburg effect of OC cells mainly through two mechanisms. On the one hand, SIK2 upregulated the expression of HIF-1α by activating the PI3K/AKT signaling pathway, which directly upregulated the transcription of major glycolytic genes to promote glycolysis. On the other hand, SIK2 promoted mitochondrial fission through phosphorylation of Drp1 at Ser616 site, which inhibited the mitochondrial oxidative phosphorylation. In addition, SIK2 promoted growth and metastasis of OC cells by promoting cell proliferation and inhibiting cell apoptosis, as well as enhancing the epithelial-mesenchymal transition. Moreover, the SIK2-mediated reprogramming of glucose metabolism played a critical role in growth and metastasis of OC cells. Collectively, our findings demonstrate that SIK2 is a crucial regulator of glucose metabolism in OC cells through activation of PI3K/AKT/HIF-1α pathway and Drp1 phosphorylation-mediated mitochondrial fission, which plays a critical oncogenic role in OC cells.

Three-dimensional oxabicycloheptene sulfonate targets the homologous recombination and repair programmes through estrogen receptor α antagonism Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Jun Wu, Jing Yan, Pingping Fang, Hai-bing Zhou, Kaiwei Liang, Jian Huang Abstract Selective estrogen receptor modulators (SERMs) are a class of structurally diverse compounds, which have been extensively used to treat hormone-responsive cancers due to their unique partially agonistic and antagonistic properties toward estrogen receptors. Our previous studies have identified a three-dimensional SERM, oxabicycloheptene sulfonate (OBHS), as an estrogen receptor α (ERα) ligand, which is effective for the prevention and treatment of estrogen-dependent endometriosis in vivo. Here, using genome-wide ChIP-seq and RNA-seq analysis, we report that OBHS rapidly induces genome-wide ERα occupancy and acts as a partial agonist and antagonist for ERα. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules, resulting in increased DNA damage, apoptosis and cell cycle arrest, inducing synthetic lethality with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib through ERα antagonism. Mechanistically, OBHS impairs the RNA polymerase II (Pol II) loading at the promoters of estrogen-responsive HRR genes. Furthermore, combination therapy of OBHS with olaparib significantly reduces the tumour burden and delays the progression of breast cancer in vivo. Together, our studies not only characterise a novel SERM which uniquely targets the homologous recombination and repair programmes through ERα antagonism but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib for ERα-responsive cancers.

MiR-337–3p suppresses proliferation of epithelial ovarian cancer by targeting PIK3CA and PIK3CB Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Zhen Zhang, Luoyan Zhang, Bin Wang, Ran Wei, Yunxia Wang, Jipeng Wan, Chi Zhang, Lin Zhao, Xiaoxiao Zhu, Yunhong Zhang, Chu Chu, Qiang Guo, Xunqiang Yin, Xia Li Abstract Epithelial ovarian cancer (EOC) is responsible for nearly 140,000 deaths worldwide each year. MicroRNAs play critical roles in cancer development and progression. The function of microRNA miR-337–3p has been described in various cancers. However, the biological role of miR-337–3p and its molecular mechanisms underlying EOC initiation and progression have not been reported. Here, we reported that the expression of miR-337–3p is down-regulated in EOC tissues and low expression of miR-337–3p is correlated with advanced pathological grade for patients. Ectopic expression of miR-337–3p inhibited proliferation and induced apoptosis and cell cycle arrest in G0/G1 phase of EOC cells. PIK3CA and PIK3CB were revealed to be direct targets of miR-337–3p for reducing the activation of PI3K/AKT signaling pathway. PIK3CA and PIK3CB were discovered to affect cell proliferation of EOC cells in combination, and only when overexpressed simultaneously in miR-337-3p-expressing cells, could fully restore cell proliferation. In vivo investigation confirmed that miR-337–3p is a tumor suppressor that control expression of PIK3CA and PIK3CB encoded protein: p110α and p110β. Altogether, our results demonstrate that miR-337–3p is a tumor suppressor in EOC that inhibits the expression of PIK3CA and PIK3CB.

Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2 Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Jie Lv, Sheng Zhang, Huita Wu, Jing Lu, Yuyan Lu, Fuqiang Wang, Wenxiu Zhao, Ping Zhan, Junjiang Lu, Qinliang Fang, Chengrong Xie, Zhenyu Yin Abstract Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo. In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC.

KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Yingying Tong, Dong Guo, Dong Yan, Chunmin Ma, Fei Shao, Yugang Wang, Shudi Luo, Liming Lin, Jingjing Tao, Yuhui Jiang, Zhimin Lu, Dongming Xing Abstract Frequently occurring histone lysine succinylation is a newly identified histone modification that can be regulated by KAT2A histone succinyltransferase, which is also a histone acetyltransferase. KAT2A histone succinyltransferase activity is important for tumorigenesis; however, the mechanism underlying this tumor-promoting effect remains elusive. Here we demonstrate that KAT2A is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens and positively correlated with advanced stages of PDAC and short patients’ survival. In addition, KAT2A expression in PDAC specimens is correlated with 14-3-3ζ expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3-3ζ) to promote YWHAZ mRNA and 14-3-3ζ expression, thereby preventing β-catenin degradation. Expression of succinyltransferase activity-defective KAT2A Y645A reduces H3K79 succinylation and 14-3-3ζ expression, leading to decreased β-catenin stability and subsequently decreased expression of cyclin D1, c-Myc, GLUT1, and LDHA. KAT2A-mediated 14-3-3ζ and β-catenin expression promotes glycolysis, cell proliferation, and migration and invasion of PDAC cells with epithelial-to-mesenchymal transition. These findings reveal a novel and instrumental role of KAT2A-mediated histone succinylation in regulation of gene expression and β-catenin stability to promote tumor cell proliferation and invasion.

Mouse models of thyroid cancer: Bridging pathogenesis and novel therapeutics Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Yuchen Jin, Min Liu, Ri Sa, Hao Fu, Lin Cheng, Libo Chen Abstract Due to a global increase in the incidence of thyroid cancer, numerous novel mouse models were established to reveal thyroid cancer pathogenesis and test promising therapeutic strategies, necessitating a comprehensive review of translational medicine that covers (i) the role of mouse models in the research of thyroid cancer pathogenesis, and (ii) preclinical testing of potential anti-thyroid cancer therapeutics. The present review article aims to: (i) describe the current approaches for mouse modeling of thyroid cancer, (ii) provide insight into the biology and genetics of thyroid cancers, and (iii) offer guidance on the use of mouse models for testing potential therapeutics in preclinical settings. Based on research with mouse models of thyroid cancer pathogenesis involving the RTK, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, SRC, and JAK-STAT signaling pathways, inhibitors of VEGFR, MEK, mTOR, SRC, and STAT3 have been developed as anti-thyroid cancer drugs for “bench-to-bedside” translation. In the future, mouse models of thyroid cancer will be designed to be ‘‘humanized” and “patient-like,” offering opportunities to: (i) investigate the pathogenesis of thyroid cancer through target screening based on the CRISPR/Cas system, (ii) test drugs based on new mouse models, and (iii) explore the underlying mechanisms based on multi-omics.

Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Mark Bates, Fiona Furlong, Michael F. Gallagher, Cathy D. Spillane, Amanda McCann, Sharon O'Toole, John J. O'Leary Abstract MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer.

CircRNA cRAPGEF5 inhibits the growth and metastasis of renal cell carcinoma via the miR-27a-3p/TXNIP pathway Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Qiong Chen, Tao Liu, Yi Bao, Tangliang Zhao, Jie Wang, Hui Wang, Anbang Wang, Xinxin Gan, Zhenjie Wu, Linhui Wang Abstract Circular RNAs (circRNAs) are reported to act as important regulators in cancers. CircRNA RAPGEF5 (cRAPGEF5) is derived from exons 2–6 of the RAPGEF5 gene and may promote papillary thyroid cancer progression. However, the role of cRAPGEF5 in renal cell carcinoma (RCC) remains unclear. In this study, we found cRAPGEF5 to be significantly downregulated in RCC tissues. Among 245 RCC cases, cRAPGEF5 downregulation correlated positively with aggressive clinical characteristics and independently predicted poor overall survival and recurrence-free survival. Functional assays demonstrated that cRAPGEF5 suppresses RCC proliferation and migration in vitro and in vivo. Mechanistically, RNA Immunoprecipitation and circRNA in vivo precipitation assays showed that cRAPGEF5 functions as a sponge of oncogenic miR-27a-3p, which targets the suppressor gene TXNIP. Interactions between miR-27a-3p and cRAPGEF5 or TXNIP were confirmed by dual-luciferase reporter assays. In conclusion, cRAPGEF5 plays a role in suppressing RCC via the miR-27a-3p/TXNIP pathway and may serve as a promising prognostic biomarker and novel therapeutic target for RCC patients.

The influence of patient sex on clinical approaches to malignant glioma Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Silvia Matteoni, Claudia Abbruzzese, Veronica Villani, Walter Malorni, Andrea Pace, Paola Matarrese, Marco G. Paggi Abstract Gliomas are tumors that originate from the glial tissue, thus involving the central nervous system with varying degrees of malignancy. The most aggressive and frequent form is glioblastoma multiforme, a disease characterized by resistance to therapies, frequent recurrences, and extremely poor median survival time. Data on overall glioma case studies demonstrate clear sex disparities regarding incidence, prognosis, drug toxicity, clinical outcome, and, recently, prediction of therapeutic response. In this study, we analyze data in the literature regarding malignant glioma, mainly glioblastoma multiforme, focusing on epidemiological and clinical evaluations. Less discussed issues, such as the role of viral infections, energy metabolism, and predictive aspects concerning the possible use of dedicated therapeutic approaches for male or female patients, will be reported together with different estimated pathogenetic mechanisms underlying astrocyte transformation and glioma chemosensitivity. In this era, where personalized/precision medicine is the most important driver for targeted cancer therapies, the lines of evidence discussed herein strongly suggest that clinical approaches to malignant glioma should consider the patient's sex. Furthermore, retrospectively revising previous clinical studies considering patient sex as a crucial variable is recommended.

Reduction of circular RNA Foxo3 promotes prostate cancer progression and chemoresistance to docetaxel Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Zhiyuan Shen, Le Zhou, Chao Zhang, Jun Xu Abstract Dysregulation of circular RNA Foxo3 (circFoxo3) has been reported to be involved in breast cancer and non-small lung cancer progression. However, little is known about the role of circFoxo3 in prostate cancer, which the present study seeks to investigate. CircFoxo3 expression was analyzed in 22 low-grade prostate cancer samples, 24 high-graded prostate cancer samples, and 18 normal prostate tissues, finding that its quantity was significantly decreased in high-graded compared to low-grade prostate cancer and normal prostate tissues. CircFoxo3 inhibited prostate cancer cell survival, migration, invasion and chemoresistance to docetaxel, which was related to circFoxo3's repression of Foxo3 and EMT. Silencing circFoxo3 expression promoted prostate cancer cell survival, migration, invasion and chemoresistance to docetaxel, as well as the positive effects of androgen on prostate cancer viability. Delivery of circfoxo3 enhanced chemosensitivity to docetaxel of prostate tumor-bearing mice and prolonged the life span of mice, while reduction with siRNAs promoted chemoresistance to docetaxel and shorted the life span of the tumor-bearing mice. Targeting circFoxo3/Foxo3/EMT may provide an applicable strategy for exploring potential prognostic and therapeutic approaches for prostate cancer.