In colonic ρ0 (rho0) cells reduced mitochondrial function mediates transcriptomic alterations associated with cancer.

Harrison M Penrose,Zachary F Pursell,Chloe Cable,Suzana D Savkovic,Nate Ungerleider,Susan E Crawford,Erik K Flemington,Sandra Heller,Hani Nakhoul,Melody Baddoo

doi:10.18632/oncoscience.386

Harrison M Penrose, Zachary F Pursell + Show 8 more

Open Access

https://doi.org/10.18632/oncoscience.386

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Abstract

BackgroundMitochondrial reprogramming has emerged as a hallmark of cancer pathobiology. Although it is believed this reprogramming is essential for cancer cells to thrive, how it supports cancer pathobiology is unclear. We previously generated colonic ρ0 (rho0) cells with reduced mitochondrial energy function and acquired their transcriptional signature. Here, we utilized a bioinformatics approach to identify their changes linked to cancer pathobiology.MethodsHuman colon cancer HCT116 cells, control and ρ0, were used for qPCR. Bioinformatics analysis: GeneCards, Kaplan-Meier Survival, GENT, cBioPortal.ResultsThe colonic ρ0 transcriptome was linked with proliferation, DNA replication, survival, tumor morphology, and cancer. Among differentially expressed transcripts, 281 were regulators or biomarkers of human colon cancer especially those with inflammatory microsatellite instability (MSI). We identified and validated novel transcripts in ρ0 cells with altered expression in human colon cancer. Among them DGK1, HTR7, FLRT3, and ZBTB18 co-occurred with established regulators of human colon cancer pathobiology. Also, increased levels of DGKI, FLRT3, ZBTB18, and YPEL1 as well as decreased levels of HTR7, and CALML6 were linked to substantially poorer patient survival.ConclusionWe identified established and novel regulators in colon cancer pathobiology that are dependent on mitochondrial energy reprogramming and linked to poorer patient survival.

Highlights

Metabolic reprogramming has emerged as a new hallmark of cancer progression validating cancer as a metabolic disease [1, 2]
We identified established and novel regulators in colon cancer pathobiology that are dependent on mitochondrial energy reprogramming and linked to poorer patient survival
Since this supports a critical role for reduced mitochondrial energy function in colon cancer pathobiology, we analyzed in colonic ρ0 cells with decreased mitochondrial ATP production [21] if differentially expressed (DE) transcripts were associated with human colon cancer

Summary

Results

The colonic ρ0 transcriptome was linked with proliferation, DNA replication, survival, tumor morphology, and cancer. 281 were regulators or biomarkers of human colon cancer especially those with inflammatory microsatellite instability (MSI). We identified and validated novel transcripts in ρ0 cells with altered expression in human colon cancer. Among them DGK1, HTR7, FLRT3, and ZBTB18 co-occurred with established regulators of human colon cancer pathobiology. Increased levels of DGKI, FLRT3, ZBTB18, and YPEL1 as well as decreased levels of HTR7, and CALML6 were linked to substantially poorer patient survival

INTRODUCTION

RESULTS AND DISCUSSION

MATERIAL AND METHODS