Low oxygen levels are crucial for breast cancer progression

About Authors

Dr. Ashok Cheemala obtained his Ph.D. in Cancer Biology under Prof. Sudhakar Baluchamy at the department of Biotechnology, Pondicherry University, where he studied the transcriptional regulation of epigenetic regulators in breast and cervical cancer. Later he joined the Indian Institute of Science Education and Research (IISER) Bhopal for the Postdoctoral program. He worked in Dr. Sanjeev Shukla’s lab at the Department of Biological Sciences. During his Postdoctoral program, Dr. Ashok studied hypoxia-driven epigenetic reprogramming that regulates the expression of a splicing factor that contributes to breast cancer progression. His research unveils how the expression of a significant splicing regulator called ESRP1 is spatiotemporally regulated to orchestrate transcriptome at different stages of breast cancer progression. Dr. Ashok is currently working as a Postdoctoral Fellow in the Center for Vascular Biology, UConn Health, Connecticut, USA, with Dr. Patrick Murphy, focusing on the interrelationship between Alzheimer’s disease and cardiac dysfunction: the brain–heart continuum. 

Dr. Neha Ahuja is an aspiring science writer. She obtained her MSc in Biotechnology from Savitribai Phule Pune University. Dr. Neha then joined the Indian Institute of Science Education and Research, Bhopal, where she did her Ph.D. in the Department of Biological Sciences under Associate Prof. Dr. Sanjeev Shukla. During her Ph.D., she worked on hypoxia-regulated alternative splicing changes in breast tumorigenesis. She explored the hypoxia-mediated mechanisms behind the alternative splicing shift of a critical gene, hMENA, towards a more invasive isoform in breast cancer cells. She also explored the regulatory mechanisms driving the expression of an essential splicing factor, ESRP1, during breast cancer progression.

How would you explain your research outcomes to the non-scientific community?

Research in ovarian, colorectal, and prostate cancer has recognized the upregulation of the ESRP1 gene as a crucial cancer-promoting route for the cells. The spliceome of the cancer cells alters to support unregulated voracious cell division on account of an increase in ESRP1 expression. The observation that ESRP1 is drastically upregulated in breast tumors compared to the surrounding normal tissue leads us towards the previously unknown mechanisms behind this elevated expression. In our promoter analysis and further experiments, E2F1 appeared as the transcription factor responsible for ESRP1 upregulation. The expression of E2F1 was itself found to be elevated in breast tumor tissue.

Our previous work demonstrated the downregulation of ESRP1 in hypoxic tumor tissue. Due to constrained oxygen supply, the oxygen-deficient condition arises in parts of the tumor owing to the improper blood supply, called a hypoxic environment. Paradoxically, the expression of E2F1 was found to increase under hypoxia even though the downstream ESRP1 gene expression diminished. This lead to speculations of epigenetic regulation of ESRP1 under hypoxia. With respect to the same, methylation at the ESRP1 promoter was found to increase under hypoxia. Due to their intricate opposing relation, the hydroxymethylation status at the promoter was also examined to find that the 5hmC marks decreased at the promoter of ESRP1. This observation coincided with another study that demonstrated the depletion of Tet activity under hypoxia. Under hypoxia, the cells decreased the hydroxymethylation marks at the ESRP1 promoter due to the diminished Tet activity, allowing de novo methyltransferases to place the 5mC marks back at the ESRP1 promoter. This decreases the ESRP1 expression, transforming the cells to mesenchymal nature by altering the splice-isoforms.

Hence, when the cells need to proliferate uncontrollably, they upregulate ESRP1 to support their division. Then again, when the cells experience hypoxic stress, they restrain ESRP1 expression to support epithelial to mesenchymal transformation so that the cells can now gain motility to escape the hypoxic niche. This is how the cells reach the bloodstream to spread cancer. Our current research can lead to a more comprehensive understanding of the complex mechanisms in breast tumors, which direct its spread. It alludes to the need for more strategic breast cancer therapy.

Figure 1: The elevated levels of transcriptional activator E2F1 and gain of 5hmC marks on the ESRP1 promoter govern the ESRP1 upregulation. However, ESRP1 expression is severely diminished within the hypoxic tumor niche despite a high E2F1 level. Mechanistically, hypoxia-driven reduction in TET3 activity coerces the E2F1 binding site on the ESRP1 promoter to lose 5hmC marks while gaining DNMT3A/3B-dependent 5mC marks. Additionally, elevated E2F1 regulates the hypoxia-specific spliceome by inducing SRSF7 expression.

How do these findings contribute to your research area?

Breast cancer is a biologically and molecularly heterogeneous disease that originated from the breast. We expect that promoting a fuller and deeper understanding of the mechanisms of breast cancer progression at molecular, cellular, and systems levels across the broad spectrum of pathologies may lead to potential prevention and treatment strategies to decrease the burden of breast cancer progression. Our findings provide previously unreported mechanistic insights into the plastic nature of ESRP1 expression and insinuate important implications in therapeutics targeting breast cancer progression.

Our findings provide previously unreported mechanistic insights into the plastic nature ofESRP1 expression and insinuate important implications in therapeutics targeting breast cancer progression.

What was the exciting moment during your research?

AC: There was not just a single eureka moment that I can pinpoint. I enjoyed every moment that I spent in my lab. Results and the challenges as they came across during the journey.

NA: There were many exciting moments when we were working on this project. Precisely, I would say there were two significant thrilling moments; one is when we discovered E2F1 as the transcription factor of ESRP1. Later, when we observed that ESRP1 expression was regulated differently under hypoxia, the realization that epigenetic mechanisms were behind ESRP1 regulation was quite fascinating.

What do you hope to do next?

AC: Currently, I am working as a Postdoctoral fellow in Dr. Patrick Murphy’s lab, where my primary objective is to understand and explore the interrelationship between Alzheimer’s disease and cardiac dysfunction. Alzheimer’s disease is a progressive neurologic disorder that causes the brain to shrink and brain cells to die. It’s a progressive neurodegenerative disorder that accounts for about 70% of all dementia cases. Currently, there is no treatment and prevention for this fatal disease. Worldwide, 50 million people live with dementia, and nearly 10 million new cases are being reported every year. Growing evidence supports a strong and likely causal association between cardiovascular disease, and its risk factors, with the incidence of cognitive decline and Alzheimer’s disease. I firmly believe that a thorough understanding and exploration of the disease’s etiology might lead to exciting and novel insights which might be further studied to extract potential prevention and treatment strategies to decrease the burden of Alzheimer’s disease.

NA: Currently, I am working towards a better reach of scientific discoveries, past, present, and future. As I have mentioned beforehand, I want the efforts, accidental achievements, and sacrifices of scientists, the hardships they have faced while working on a hypothesis, basically, all scientific stories, to reach citizens globally.

Where do you seek scientific inspiration from?

AC: My scientific inspiration comes from my curiosity to know more about new things. All scientific discoveries are unique, and some are truly life-changing. The simple discovery of penicillin, an antibiotic agent by Alexander Fleming, and the smallpox vaccine by Edward Jenner has saved millions of lives. These two scientific discoveries constantly motivate me to seek the unknown and contribute positively to scientific research and society in general.

NA: I was always very inquisitive. This behavior was further encouraged by my mentors during the undergraduate program. They keep inspiring me to date. I always felt the need to work towards a better society through my profession. Hence when I realized my interest in biology, I wanted to gain insights into the research and scientific world as science can help to better comprehend the world around us.

How do you intend to help Indian science improve?

AC: In my opinion, Indian science is reaching new heights every day and showcasing cutting-edge scientific research globally, such as the make in INDIA program. Educating young minds towards science and providing the basic facilities for science and technology would greatly benefit the growth of Indian science.

NA: I believe Indian science is flourishing and Indian scientists are setting new benchmarks. I strongly feel that interest in scientific research can be instilled at a young age, and there is a need for us Indians to work in that direction so that young intellectual minds can see science as a career. I want to work towards the same in the future, so that science and scientific understanding reach every country’s household, as I believe that education begins at home.

Reference

Ashok, C., Ahuja, N., Natua, S., Mishra, J., Samaiya, A., & Shukla, S. (2021). E2F1 and epigenetic modifiers orchestrate breast cancer progression by regulating oxygen-dependent ESRP1 expression. Oncogenesis, 10(8), 1-10.

Edited by: Vikramsingh Gujar

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