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Altered metabolism is a hallmark of cancer, and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors. It is well recognized that long noncoding RNAs (lncRNAs) regulate energy metabolism in cancer. However, lncRNA‐mediated posttranslational modifications and metabolic reprogramming are unclear at present. In this review, we summarized the current understanding of the interactions between the alterations in cancer‐associated energy metabolism and the lncRNA‐mediated posttranslational modifications of metabolic enzymes, transcription factors, and other proteins involved in metabolic pathways. In addition, we discuss the mechanisms through which these interactions contribute to tumor initiation and progression, and the key roles and clinical significance of functional lncRNAs. We believe that an in‐depth understanding of lncRNA‐mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs.

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid–liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 ( SNHG9 ) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9 ) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene ( AGPG ) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG . Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target. PFKFB3 enhances glycolysis to promote cancer cell proliferation. Here, the authors identify a long noncoding RNA in esophageal squamous cell carcinoma, AGPG , which interacts with PFKFB3 and promotes its stability, leading to increased glycolysis and proliferation.

Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron–sulfur (Fe–S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.

Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo . Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N 6 -methyladenosine (m 6 A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS -IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.

Accurate risk stratification for patients with stage II/III colon cancer is pivotal for postoperative treatment decisions. Here, we aimed to identify and validate a circRNA‐based signature that could improve postoperative prognostic stratification for these patients. In current retrospective analysis, we included 667 patients with R0 resected stage II/III colon cancer. Using RNA‐seq analysis of 20 paired frozen tissues collected postoperation, we profiled differential circRNA expression between patients with and without recurrence, followed by quantitative validation. With clinical information, we generated a four‐circRNA‐based cirScore to classify patients into high‐risk and low‐risk groups in the training cohort. The patients with high cirScores in the training cohort had a shorter disease‐free survival (DFS) and overall survival (OS) than patients with low cirScores. The prognostic capacity of the classifier was validated in the internal and external cohorts. Loss‐of‐function assays indicated that the selected circRNAs played functional roles in colon cancer progression. Overall, our four‐circRNA‐based classifier is a reliable prognostic tool for postoperative disease recurrence in patients with stage II/III colon cancer. Synopsis Novel molecular biomarkers allowing for better prognostic stratification of patients with stage II/III colon cancer are urgently needed. In this study, a circRNA‐based signature (cirScore) was identified and validated to improve postoperative risk‐stratification for these patients. Dysregulated circRNAs showed strong classification capacities in distinguishing between recurrent and nonrecurrent colon cancer patients. The proposed four‐cirRNA‐based cirScore can effectively classify patients with stage II/III colon cancer into groups with low and high risks of disease recurrence. The loss‐of‐function assay indicated that the representative circRNAs plays functional roles in the sophisticated regulation of colon cancer progression. Nomograms incorporating the cirScore with existing risk factors achieved excellent accuracy for predicting disease‐free and overall survival for patients with stage II/III colon cancer. Graphical Abstract Novel molecular biomarkers allowing for better prognostic stratification of patients with stage II/III colon cancer are urgently needed. In this study, a circRNA‐based signature (cirScore) was identified and validated to improve postoperative risk‐stratification for these patients.

Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013 ), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM -NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM- NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development. Iron metabolism dysregulation is associated with various diseases including cancer. Here, the authors show that one iron-triggered lncRNA LncRIM regulates cellular iron metabolism effectively by wiring up the Hippo-YAP  signaling pathway and promotes breast cancer development.

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state. In liver metastasis of cancer, the inflammatory macrophage niche is dominated by both circulating monocytes and local expansion, but the nature and dynamic of this niche is still unclear. Here the authors use mouse genetic models and lineage-tracing tools to show that, under the condition of monocyte depletion, Kupffer cells pursue epigenetic reprogramming to contribute to this niche.