Stress Responses as Master Keys to Epigenomic Changes in Transcriptome and Metabolome for Cancer Etiology and Therapeutics

ABSTRACT

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anticancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anticancer treatment scenario involving the imposition of stress to target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.

KEYWORDS:

• epigenetic response
• oxidative stress
• DNA damage
• hypoxia
• hyperthermia
• nutrient deprivation

Declaration of Interests

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

We thank the members of our laboratories for insightful discussions. Regretfully, many excellent papers could not be included here due to space limitations and our focus on results with which we are most familiar for the exemplary work cited within this broad area.

This research was supported by the National Institutes of Health (NIH; grants P01 CA092584, R35 CA220430, and P30 GM124169) and the Robert A. Welch Chemistry Chair and Cancer Prevention and Research Institute of Texas (CPRIT; grant RP180813) to J.A.T. This study used computing resources from the Texas Advanced Computing Center (TACC) at the University of Texas in Austin, TX. C.D. acknowledges support from Basic and Applied Research in Biophysics and Material Science (RSI 4002) by the Department of Atomic Energy (DAE), Government of India, SwarnaJayanti Fellowship (DST/SJF/LSA-02/2017-18), Department of Science and Technology, and an S. Ramachandran National Bioscience Award for Career Development 2019 (BT/HRD-NBA-NWB/38/2019-20), Department of Biotechnology.