RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell-type

The human terminal uridyl transferases TUT4 and TUT7 (TUT4/7) catalyse the additions of uridines at the 3′ end of RNAs, including the precursors of the tumour suppressor miRNA let-7 upon recruitment by the oncoprotein LIN28A. As a consequence, let-7 family miRNAs are downregulated. Disruption of this TUT4/7 activity inhibits tumorigenesis. Hence, targeting TUT4/7 could be a potential anti-cancer therapy. In this study, we investigate TUT4/7-mediated RNA regulation in two cancer cell lines by establishing catalytic knockout models. Upon TUT4/7 mutation, we observe a significant reduction in miRNA uridylation, which results in defects in cancer cell properties such as cell proliferation and migration. With the loss of TUT4/7-mediated miRNA uridylation, the uridylated miRNA variants are replaced by adenylated isomiRs. Changes in miRNA modification profiles are accompanied by deregulation of expression levels in specific cases. Unlike let-7s, most miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. Additionally, we identify TUT4/7-regulated cell-type-specific miRNA clusters and deregulation in their corresponding mRNA targets. Expression levels of miR-200c-3p and miR-141-3p are regulated by TUT4/7 in a cancer cell-type-specific manner. Subsequently, BCL2 which is a well-established target of miR-200c is upregulated. Therefore, TUT4/7 loss causes deregulation of miRNA-mRNA networks in a cell-type-specific manner. Understanding the underlying biology of such cell-type-specific deregulation will be an important aspect of targeting TUT4/7 for potential cancer therapies.

RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell-type

The human terminal uridyl transferases TUT4 and TUT7 (TUT4/7) catalyse additions of uridines at the 3′ end of RNAs such as the precursors of the tumour suppressor miRNA let-7, upon recruitment by the oncoprotein LIN28A. Consequently, let-7 family miRNAs are downregulated. Disruption of this TUT4/7 activity inhibits tumorigenesis and hence targeting TUT4/7 can be a potential anti-cancer therapy. In this study, we investigate TUT4/7-mediated RNA regulation in two cancer cell lines by establishing catalytic knockout models. Upon TUT4/7 mutation, we observe a significant reduction in miRNA uridylation, which results in defects in cancer cell properties such as cell proliferation and migration. With the loss of TUT4/7-mediated miRNA uridylation, the uridylated miRNA variants are replaced by adenylated isomiRs. Changes in miRNA modification profiles are accompanied by deregulation of expression levels in specific cases. Unlike let-7s, most miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. Additionally, we identify TUT4/7-regulated cell-type-specific miRNA clusters and deregulation in their corresponding mRNA targets. Expression levels of miR-200c-3p and miR-141-3p are regulated by TUT4/7 in a cancer cell type specific manner. Subsequently, BCL2 which is a well-established target of miR-200c is upregulated. Therefore, TUT4/7 loss triggers deregulation of miRNA-mRNA networks in a cell-type-specific manner. Understanding of the underlying biology of such cell-type-specific deregulation will be key when targeting TUT4/7 for cancer therapy.

Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.

Clock genes and the role of melatonin in cancer cells: an overview

Circadian rhythms control most biological processes in every organism and their disruption or an aberrant function in the expression of clock genes are associated with a number of cancers including some hormone-dependent and independent cancers. The processes involved in carcinogenesis and tumor progression are complex, but understanding the daily profiles of the core clock genes and their clock-controlled genes is essential to evaluate specifically the molecular program of the cancer phenotype; this may be helpful in providing a more realistic strategy for both diagnosis and treatment during the course of the disease. Because melatonin production and secretion oscillates rhythmically through the light:dark cycle and is related to the circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes), its regulatory role on clock genes in cancer cells may bring additional evidence regarding the mechanism(s) by which melatonin is involved. Mechanistically, melatonin acts via proteasome inhibition and sirtuins to indirectly modulate clock genes in cancer; however, melatonin seems to be capable of directly altering the expression of clock genes to affect cancer development. Depending on cancer cell type, melatonin might up or downregulate specific clock genes to control cell cycle, survival, repair mechanisms, etc. In parallel, melatonin exerts pro-apoptotic, anti-proliferative and pro-oxidative effects, metabolic shifting, reduction in neovasculogenesis and inflammation, and restores chemosensitivity of cancer cells. Finally, melatonin improves the life quality of patients. This review focuses on the main functions of melatonin on clock genes, and reviews, from a clinical and experimental standpoint, how melatonin regulates the expression of clock genes in some prevalent cancer types such as breast, prostate, liver, and colon cancers, leukemia and melanoma. We further emphasized possible signaling mechanisms whereby melatonin interferes with clockwork genes and circadian-controlled genes within cancer cells.