Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a broadly expressed lncRNA involved in many aspects of cellular processes. To further delineate the underlying molecular mechanism, we employed a high-throughput strategy to characterize the interacting proteins of MALAT1 by combining RNA pull-down, quantitative proteomics, bioinformatics, and experimental validation. Our approach identified 127 potential MALAT1-interacting proteins and established a highly connected MALAT1 interactome network consisting of 788 connections. Gene ontology annotation and network analysis showed that MALAT1 was highly involved in five biological processes: RNA processing; gene transcription; ribosomal proteins; protein degradation; and metabolism regulation. The interaction between MALAT1 and depleted in breast cancer 1 (DBC1) was validated using RNA pull-down and RNA immunoprecipitation. Further mechanistic studies reveal that MALAT1 binding competes with the interaction between sirtuin1 (SIRT1) and DBC1, which then releases SIRT1 and enhances its deacetylation activity. Consequently, the deacetylation of p53 reduces the transcription of a spectrum of its downstream target genes, promotes cell proliferation and inhibits cell apoptosis. Our results uncover a novel mechanism by which MALAT1 regulates the activity of p53 through the lncRNA–protein interaction.

Cervical cancer is one of the most common malignant tumors and the leading cause of cancer-related mortality in women. Persistent cervical infection by high-risk human papillomavirus (hrHPV) is related to cervical cancer. MicroRNAs could regulate autophagy caused by viral infection. The aim of the present study was to investigate the regulation of autophagy by miR-155-5p in cervical cancer. In HPV+ human cervical lesion tissues, miR-155-5p expression was found to be markedly decreased. Compared to C33A cancer cells (HPV-), the miR-155-5p expression was significantly lower in Siha and HeLa cells (HPV+), which are both hrHPV positive. The level of autophagy was higher in C33A cells than in Siha and HeLa cells. In addition, in C33A, Siha and HeLa cervical cancer cells, miR-155-5p overexpression promoted autophagy, whereas miR-155-5p downregulation had the opposite effects. Furthermore, miR-155-5p downregulation suppressed LC3 and promoted P62 protein expression in C33A cells through promoting the PDK1/mTOR pathway, whereas miR-155-5p overexpression recovered LC3 and suppressed P62 protein expression by suppressing PDK1/mTOR signaling. Taken together, our results indicate the importance of miR-155-5p in cervical cancer cells and suggest a novel mechanism of hrHPV in promoting cervical lesions.

S: Glycine decarboxylase (GLDC) belongs to the glycine cleavage system and is involved in one-carbon metabolism. We previously reported that GLDC downregulation enhances hepatocellular carcinoma (HCC) progression and intrahepatic metastasis through decreasing ROS-mediated ubiquitination of cofilin. The role of autophagy in cancer metastasis is still controversial. Redox-dependent autophagy largely relies on the magnitude and the rate of ROS generation. Thus, we aimed to explore the role of GLDC in cellular autophagy during HCC progression. We showed that a high GLDC expression level is associated with better overall survival and is an independent factor for the favorable prognosis of HCC patients. GLDC overexpression significantly induced cell autophagy, whereas GLDC downregulation reduced cell autophagy. Of note, GLDC is the post-transcriptional target of miR-30d-5p. GLDC overexpression could rescue miR-30d-5p-mediated cell metastasis and increase autophagy. Furthermore, upregulation of GLDC could significantly decrease p62 expression and impair intrahepatic metastasis in vivo. Taken together, our results suggest that GLDC may play an important role to increasing miR-30d-5p-reduced autophagy to suppress HCC progress.

Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs (LIM domain kinases), and SSH1 (slingshot family protein phosphate 1). Ubiquitination, as a ubiquitous post-transcriptional modification, deceases protein levels of actin cytoskeleton regulatory factors and thereby modulates the actin cytoskeleton. There is increasing evidence showing cytoskeleton regulation by long noncoding RNAs (lncRNAs) in cancer metastasis. However, which E3 ligases are activated for the ubiquitination of actin-cytoskeleton regulators involved in tumor metastasis remains to be fully elucidated. Moreover, it is not clear how lncRNAs influence the expression of actin cytoskeleton regulators. Here, we summarize physiological and pathological mechanisms of lncRNAs and ubiquitination control mediators of actin cytoskeleton regulators which that are involved in tumorigenesis and tumor progression. Finally, we briefly discuss crosstalk between ubiquitination and lncRNA control mediators of actin-cytoskeleton regulators in cancer.

Invasion and intrahepatic metastasis are major factors of poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we show that increased Src homolog and collagen homolog 3 (Shc3) expression in malignant HCC cell lines associate with HCC invasion and metastasis. Shc3 (N-Shc) was significantly upregulated in tumors of 33 HCC patient samples as compared with adjacent normal tissues. Further analysis of 52 HCC patient samples showed that Shc3 expression correlated with microvascular invasion, cancer staging, and poor prognosis. Shc3 interacted with major vault protein, resulting in activation of MEK1/2 and ERK1/2 independently of Shc1 and c-Raf; this interaction consequently induced epithelial–mesenchymal transition and promoted HCC cell proliferation and metastasis. The observed increase in Shc3 levels was due to demethylation of its upstream promoter, which allowed c-Jun binding. In turn, Shc3 expression promoted c-Jun phosphorylation in a positive feedback loop. Analysis of metastasis using a tumor xenograft mouse model further confirmed the role of Shc3 in vivo. Taken together, our results indicate the importance of Shc3 in HCC progression and identify Shc3 as a novel biomarker and potential therapeutic target in HCC. Significance: Ectopic expression of Shc3 forms a complex with MVP/MEK/ERK to potentiate ERK activation and plays an important role in sorafinib resistance in HCC. Cancer Res; 78(9); 2219–32. ©2018 AACR.