Epigenetically deregulated miR-200c is involved in a negative feedback loop with DNMT3a in gastric cancer cells

Long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression, and act as important gene expression modulators. Recent evidence indicates that lncRNA neuroblastoma associated transcript 1 (NBAT1) functions as a tumor suppressor in some types of human cancers. However, its functional role in the development of gastric cancer (GC) remains unknown. The aim of this research was to investigate the clinical significance and biological functions of NBAT1 in GC. NBAT1 was found to be significantly down-regulated in GC tissue. Decreased NBAT1 expression was correlated with poor differentiation, higher tumor stage and lymph node metastasis, and poor prognosis. Functional assays showed that NBAT1 inhibited GC proliferation, migration, and invasion. NBAT1 also suppressed proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, NBAT1 interacted with Sox9, and reduced its protein stability by promoting it from polyubiquitination and proteasome-dependent degradation. Moreover, we revealed that Sox9 could occupy the NBAT1 promoter to inactivate its transcription. The negative feedback loop of NBAT1 and Sox9 continuously enhanced the suppressive effects. In conclusion, these findings suggest that feedback regulation of NBAT1 and Sox9 served as a critical effector in GC progression.

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Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

10.1101/2020.12.21.423274 ◽

2020 ◽

Author(s):

Adithya Chedere ◽

Kishore Hari ◽

Saurav Kumar ◽

Annapoorni Rangarajan ◽

Mohit Kumar Jolly

Keyword(s):

Breast Cancer ◽

Phenotypic Plasticity ◽

Cancer Cells ◽

Cell Population ◽

Negative Feedback ◽

Feedback Loop ◽

Phenotypic Switching ◽

Negative Feedback Loop ◽

Double Negative ◽

Protein Levels

AbstractAdaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.

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