Current and potential roles of RNA modification-mediated autophagy dysregulation in cancer.

Autophagy, a cellular lysosomal degradation and survival pathway, supports nutrient recycling and adaptation to metabolic stress and participates in various stages of tumor development, including tumorigenesis, metastasis, and malignant state maintenance. Among the various factors contributing to the dysregulation of autophagy in cancer, RNA modification can regulate autophagy by directly affecting the expression of core autophagy proteins. We propose that autophagy disorder mediated by RNA modification is an important mechanism for cancer development. Therefore, this review mainly discusses the role of RNA modification-mediated autophagy regulation in tumorigenesis. We summarize the molecular basis of autophagy and the core proteins and complexes at different stages of autophagy, especially those involved in cancer development. Moreover, we describe the crosstalk of RNA modification and autophagy and review the recent advances and potential role of the RNA modification/autophagy axis in the development of multiple cancers. Furthermore, the dual role of the RNA modification/autophagy axis in cancer drug resistance is discussed. A comprehensive understanding and extensive exploration of the molecular crosstalk of RNA modifications with autophagy will provide important insights into tumor pathophysiology and provide more options for cancer therapeutic strategies.

L3MBTL2-mediated CGA transcriptional suppression promotes pancreatic cancer progression through modulating autophagy.

L3MBTL2 is a crucial component of ncPRC1.6 and has been implicated in transcriptional repression and chromatin compaction. However, the repression mechanism of L3MBTL2 and its biological functions are largely undefined. Here, we found that L3MBTL2 plays a distinct oncogenic role in tumor development. We demonstrated that L3MBTL2 repressed downstream CGA through an H2AK119ub1-dependent mechanism. Importantly, the binding of the MGA/MAX heterodimer to the E-box on the CGA promoter enhanced the specific selective repression of CGA by L3MBTL2. CGA encodes the alpha subunit of glycoprotein hormones; however, we showed that CGA plays an individual tumor suppressor role in PDAC. Moreover, CGA-transcript1 (T1) was identified as the major transcript, and the tumor suppression function of CGA-T1 depends on its own glycosylation. Furthermore, glycosylated CGA-T1 inhibited PDAC, partly by repression of autophagy through multiple pathways, including PI3K/Akt/mTOR and TP53INP2 pathways. These findings reveal the important roles of L3MBTL2 and CGA in tumor development.

TSPAN1-elevated FAM110A promotes pancreatic cancer progression by transcriptionally regulating HIST1H2BK.

Background: FAM110A belongs to the FAM110 family, which mainly functions in biological processes associated with the cell cycle. However, the biological functions in which FAM110A participates are largely undefined. In particular, its potential role in cancer remains unknown. The goal of this study was to uncover the role and mechanism of FAM110A in pancreatic cancer. Methods: Based on bioinformatics databases, qPCR and Western blot assays, we verified the elevated expression level of FAM110A in PDAC. Subsequently, FAM110A, HIST1H2BK and TSPAN1 overexpression or knockdown stable transfected cells were employed for biological functions' studies to explore the role in PDAC in vitro and in vivo. RNA-Seq, Western blot and luciferase-reporter assays were used to explore mechanism of FAM110A action in PDAC, and the involved pathway was verified by tumor phenotypic rescue experiments. Results: In this study, we demonstrated for the first time that FAM110A is an oncogene that promotes cell proliferation, migration, invasion and tumorigenesis in pancreatic cancer. HIST1H2BK was identified as the downstream target of FAM110A, while the promotion effect caused by FAM110A overexpression could be abolished by HIST1H2BK knockdown. Moreover, for the first time, we revealed the oncogenic role of HIST1H2BK in pancreatic cancer, and the tumor-promoting capacity of HIST1H2BK may be associated with its regulatory effect on G9a. In addition, we demonstrated that TSPAN1 displayed a positive transcriptional regulatory effect on FAM110A. Conclusions: Collectively, FAM110A plays an oncogenic role in PDAC, and the newly identified TSPAN1/FAM110A/HIST1H2BK/G9a pathway is involved in the modulation of pancreatic cancer progression and provides a novel prognostic and therapeutic strategy for pancreatic cancer treatment.

WBSCR22 and TRMT112 synergistically suppress cell proliferation, invasion and tumorigenesis in pancreatic cancer via transcriptional regulation of ISG15.

Pancreatic cancer (PC) is one of the most aggressive and devastating types of cancer owing to its poor prognosis and deadly characteristics. It is well established that aberrations in the expression of key regulatory genes, namely tumor suppressors and oncogenes, predispose patients to progression and metastasis of PC. Upregulation of Williams­Beuren syndrome chromosomal region 22 (WBSCR22) expression, a ribosomal biogenesis factor, has been reported in multiple types of human cancer. However, the role of WBSCR22 and its underlying mechanism in PC have not been well investigated. In the present study, the tumor suppressive role of WBSCR22 was reported in PC for the first time; the results indicated that WBSCR22 overexpression (OE) significantly suppressed cellular proliferation, migration, invasion and tumorigenesis in vivo and in vitro. RNA­sequencing analysis revealed that WBSCR22 negatively regulated the transcription of interferon­stimulated gene 15 (ISG15) downstream, which is a ubiquitin­like modifier protein involved in metabolic and proteasome degradation pathways, while the antitumor function of WBSCR22­OE could be rescued by ISG15 OE. In addition, the oncogenic role of ISG15 was further confirmed in PC; its upregulation promoted the proliferation, migration, invasion and tumorigenesis of PC. Furthermore, WBSCR22 and its cofactor tRNA methyltransferase activator subunit 11­2 (TRMT112) functioned synergistically in PC, and concurrent ectopic OE of WBSCR22 and TRMT112 further promoted the tumor suppressive potential of WBSCR22 in PC. Collectively, the findings indicated that WBSCR22 played an important role in PC development and that the WBSCR22/ISG15 axis may provide a novel therapeutic strategy for PC treatment.

Ribosome 18S m6A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c­Myc translation.

Methyltransferase N6­adenosine (METTL5) is a methyltransferase that specifically catalyzes 18S rRNA N6 methylation at adenosine 1832 (m6A1832), which is located in a critical position in the decoding center, therefore suggesting its potential importance in the regulation of translation. However, the underlying mechanism of METTL5­mediated translation regulation of specific genes and its biological functions are largely undefined. To the best of our knowledge, the present study demonstrated for the first time that METTL5 was an oncogene that promoted cell proliferation, migration, invasion and tumorigenesis in pancreatic cancer. In addition, the oncogenic function of METTL5 may involve an increase in c­Myc translation, as evidenced by the fact that the oncogenic effect caused by METTL5 overexpression could be abolished by c­Myc knockdown. Notably, m6A modifications at the 5' untranslated region (5'UTR) and coding DNA sequence region (near the 5'UTR) of c­Myc mRNA played a critical role in the specific translation regulation by METTL5. In addition, it was further demonstrated that METTL5 and its cofactor tRNA methyltransferase activator subunit 11­2 synergistically promote pancreatic cancer progression. These findings revealed important roles for METTL5 in the development of pancreatic cancer and present the METTL5/c­Myc axis as a novel therapeutic strategy for treatment.

tRNA modifications and their potential roles in pancreatic cancer.

Since the breakthrough discovery of N6-methyladenosine (m6A), the field of RNA epitranscriptomics has attracted increasing interest in the biological sciences. Transfer RNAs (tRNAs) are extensively modified, and various modifications play a crucial role in the formation and stability of tRNA, which is universally required for accurate and efficient functioning of tRNA. Abnormal tRNA modification can lead to tRNA degradation or specific cleavage of tRNA into fragmented derivatives, thus affecting the translation process and frequently accompanying a variety of human diseases. Increasing evidence suggests that tRNA modification pathways are also misregulated in human cancers. In this review, we summarize tRNA modifications and their biological functions, describe the type and frequency of tRNA modification alterations in cancer, and highlight variations in tRNA-modifying enzymes and the multiple functions that they regulate in different types of cancers. Furthermore, the current implications and the potential role of tRNA modifications in the progression of pancreatic cancer are discussed. Collectively, this review describes recent advances in tRNA modification in cancers and its potential significance in pancreatic cancer. Further study of the mechanism of tRNA modifications in pancreatic cancer may provide possibilities for therapies targeting enzymes responsible for regulating tRNA modifications in pancreatic cancer.