# Downregulation of the Long Non-Coding RNA MDL1AS Alters Metabolism, Differentiation, and Radiosensitivity in NTERA2 and SH-SY5Y Cells

## TL;DR

This study shows that reducing the lncRNA MDL1AS affects metabolism, differentiation, and radiation response in two types of cancer cells differently.

## Contribution

The novel finding is that MDL1AS downregulation modulates radiosensitivity, metabolism, and differentiation in a cell-type-specific manner.

## Key findings

- MDL1AS downregulation inhibits oxidative phosphorylation in NTERA2 cells.
- MDL1AS reduction induces neuritic differentiation in SH-SY5Y cells.
- Downregulation of MDL1AS decreases radiosensitivity in NTERA2 but not in SH-SY5Y cells.

## Abstract

Tumoral heterogeneity is one of the main obstacles to fully understanding cancer biology. Long non-coding RNAs (lncRNAs) are gaining considerable interest as they are involved in many tumor-related processes. Therefore, we aimed to study the role of mitochondrial D-loop 1 antisense lncRNA (MDL1AS) in SH-SY5Y and NTERA2 cells, which represent cells with different grades of stemness and differentiation. We found that MDL1AS affects metabolism, differentiation, and response to radiation in a cell type-dependent manner. These data suggest that MDL1AS may hold potential as a predictive biomarker or even as a therapeutic target.

Background/Objectives: Non-coding RNAs provide new chances of targeting multiple oncogenic pathways. Many long non-coding RNAs (lncRNAs) are being characterized as relevant in cancer initiation, progression, and recurrence. Mitochondrial D-loop 1 antisense lncRNA (MDL1AS) is a novel lncRNA that might be important in cancer development, so the aim of this project was to understand its function in differently differentiated cancer cells. Methods: The effects of MDL1AS downregulation on the cellular behavior of NTERA2 and SH-SY5Y cell lines were studied. Results: MDL1AS reduction inhibited oxidative phosphorylation in NTERA2 cells and induced neuritic differentiation in SH-SY5Y cells. This downregulation also produced a strong DNA damage response (DDR) and an increased apoptotic signature by RNAseq analysis, and decreased proliferation in both cell lines. It also decreased radiosensitivity in NTERA2 cells but not in SH-SY5Y. Conclusions: These results suggest that MDL1AS reduction can modulate radiosensitivity, metabolism, and differentiation in a cell type-specific manner. Furthermore, MDL1AS may constitute a predictive biomarker and a molecular target for new therapies.