Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence

Abstract

Senescence induction and epithelial-mesenchymal transition (EMT) events are the opposite sides of the spectrum of cancer phenotypes. The key molecules involved in these processes may get influenced or altered by genetic and epigenetic changes during tumor progression. Double C2-like domain beta (DOC2B), an intracellular vesicle trafficking protein of the double C2 protein family, plays a critical role in exocytosis, neurotransmitter release, and intracellular vesicle trafficking. DOC2B is repressed by DNA promoter hypermethylation and functions as a tumor growth regulator in cervical cancer. To date, the molecular mechanisms of DOC2B in cervical cancer progression and metastasis is elusive. Herein, the biological functions and molecular mechanisms regulated by DOC2B and its impact on senescence and EMT are described. DOC2B inhibition promotes proliferation, growth, and migration by relieving G0/G1-S arrest, actin remodeling, and anoikis resistance in Cal27 cells. It enhanced tumor growth and liver metastasis in nude mice with the concomitant increase in metastasis-associated CD55 and CD61 expression. Inhibition of EMT and promotion of senescence by DOC2B is a calcium-dependent process and accompanied by calcium-mediated interaction between DOC2B and CDH1. In addition, we have identified several EMT and senescence regulators as targets of DOC2B. We show that DOC2B may act as a metastatic suppressor by inhibiting EMT through induction of senescence via DOC2B-calcium-EMT-senescence axis. Graphical abstract

Goji berry (Lycium barbarum) inhibits the proliferation, adhesion, and migration of oral cancer cells by inhibiting the ERK, AKT, and CyclinD cell signaling pathways: an in-vitro study

“…36 AKT activation even inhibits the expression of proapoptotic proteins, such as BAD and BAX, and allows the cancer cells to survive. 37,38 AKT can also inactivate the caspase enzymes, which are directly involved in cell apoptosis and forkhead box protein O1 (FOXO-1) expression. This also increases the risk of cell proliferation.…”

Forward single‐cell sequencing into clinical application: Understanding of ageing and rejuvenation from clinical observation to single‐cell solution

“…Understanding the genetic and epigenetic mechanisms by which health span and lifespan can be regulated, manipulated, and extended is important for identifying and validating “rejuvenating interventions”. These mechanisms include signal regulation, metabolic interference, reprogramming, heterochronic parabiosis, target‐based drugability, and senescent editing 1–3 . One of Clinical and Translational Medicine's missions is to advance spatiotemporal molecular medicine by advancing single‐cell sequencing into clinical application, translating single‐cell measurements into routine practice, and identifying disease‐specific biomarkers and therapies 4–6 .…”

“…These mechanisms include signal regulation, metabolic interference, reprogramming, heterochronic parabiosis, target-based drugability, and senescent editing. [1][2][3] One of Clinical and Translational Medicine's missions is to advance spatiotemporal molecular medicine by advancing single-cell sequencing into clinical application, translating single-cell measurements into routine practice, and identifying diseasespecific biomarkers and therapies. [4][5][6] Advanced technologies such as single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics have broad applications in clinical tissue or fluid samples to understand intra-and intercellular communications and network interactions within the tissue or within the circulation.…”

Forward single‐cell sequencing into clinical application: Understanding of ageing and rejuvenation from clinical observation to single‐cell solution

“…Understanding the genetic and epigenetic mechanisms by which healthspan and lifespan can be regulated, manipulated and extended is important for identifying and validating ‘rejuvenating interventions’. These mechanisms include signal regulation, metabolic interference, reprogramming, heterochronic parabiosis, target‐based drugability and senescent editing 1–3 . One of Clinical and Translational Medicine's missions is to advance spatiotemporal molecular medicine by advancing single‐cell sequencing into clinical application, translating single‐cell measurements into routine practice, and identifying disease‐specific biomarkers and therapies 4–6 .…”

“…These mechanisms include signal regulation, metabolic interference, reprogramming, heterochronic parabiosis, target-based drugability and senescent editing. [1][2][3] One of Clinical and Translational Medicine's missions is to advance spatiotemporal molecular medicine by advancing single-cell sequencing into clinical application, translating single-cell measurements into routine practice, and identifying disease-specific biomarkers and therapies. [4][5][6] Advanced technologies such as single-cell RNA sequencing (scRNAseq) and spatial transcriptomics have broad applications in clinical tissue or fluid samples to understand intraand intercellular communications and network interactions within the tissue or within the circulation.…”