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The expression of telomerase catalytic subunit hTERT is frequently upregulated in many cancers. Here, the authors show HoxC5 and miR-615-3p can negatively regulate hTERT to impede tumorigenesis by targeting the newly evolved cis-regulatory genomic elements of hTERT.

Incomplete knowledge of the mechanisms at work continues to hamper efforts to maximize reprogramming efficiency. Here, we present a systematic genome-wide RNAi screen to determine the global regulators during the early stages of human reprogramming. Our screen identifies functional repressors and effectors that act to impede or promote the reprogramming process. Repressors and effectors form close interacting networks in pathways, including RNA processing, G protein signaling, protein ubiquitination, and chromatin modification. Combinatorial knockdown of five repressors (SMAD3, ZMYM2, SFRS11, SAE1, and ESET) synergistically resulted in ∼85% TRA-1-60-positive cells. Removal of the novel splicing factor SFRS11 during reprogramming is accompanied by rapid acquisition of pluripotency-specific spliced forms. Mechanistically, SFRS11 regulates exon skipping and mutually exclusive splicing of transcripts in genes involved in cell differentiation, mRNA splicing, and chromatin modification. Our study provides insights into the reprogramming process, which comprises comprehensive and multi-layered transcriptional, splicing, and epigenetic machineries.

Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease.

The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While the extracellular degradation of ECM proteins has been well characterised, ECM endocytosis and its impact on cancer cell progression, migration, and metastasis is poorly understood. ECM internalisation is increased in invasive breast cancer cells, suggesting it may support invasiveness. However, current high-throughput approaches mainly focus on cells grown on plastic in 2D, making it difficult to apply these to the study of ECM dynamics. Here, we developed a high-content screening assay to study ECM uptake, based on the of use automated ECM coating for the generation of highly homogeneous ECM a pH-sensitive dye to image ECM trafficking in live cells. We identified that mitogen-activated protein kinase (MAPK) family members, MAP3K1 and MAPK11 (p38β), and the protein phosphatase 2 (PP2) subunit PPP2R1A were required for the internalisation of ECM-bound α2β1 integrin. Mechanistically, we show that down-regulation of the sodium/proton exchanger 1 (NHE1), an established macropinocytosis regulator and a target of p38, mediated ECM macropinocytosis. Moreover, disruption of α2 integrin, MAP3K1, MAPK11, PPP2R1A, and NHE1-mediated ECM internalisation significantly impaired cancer cell migration and invasion in 2D and 3D culture systems. Of note, integrin-bound ECM was targeted for lysosomal degradation, which was required for cell migration on cell-derived matrices. Finally, α2β1 integrin and MAP3K1 expression were significantly up-regulated in pancreatic tumours and correlated with poor prognosis in pancreatic cancer patients. Strikingly, MAP3K1, MAPK11, PPP2R1A, and α2 integrin expression were higher in chemotherapy-resistant tumours in breast cancer patients. Our results identified the α2β1 integrin/p38 signalling axis as a novel regulator of ECM endocytosis, which drives invasive migration and tumour progression, demonstrating that our high-content screening approach has the capability of identifying novel regulators of cancer cell invasion.