MAFF-mediated transcription regulation of redox pathways in response to radiation treatment

RESEARCH SUMMARY:

Our research focuses on determining how microenvironments affect tumour progression and radiation responses. We are specifically interested in MAFF, a bZIP transcription factor, which plays a significant role in antioxidant responses. While RT induces cell killing by direct DNA damage, approximately two-thirds of radiation damage is induced indirectly through increased production of reactive oxygen species (ROS). In addition to their role in DNA damage, ROS regulate signal transduction and redox pathways to promote tumour cell survival and expansion. To increase the efficacy of RT in killing tumour cells, we need to manipulate the redox environment of cancer cells focusing on ROS-sensing signalling pathways.

MAFF, which lacks a transactivation domain, is an essential binding partner of well-known regulators of antioxidant responses such as NRF2 and BACH1. In our recent study, we demonstrated that MAFF promotes tumour cell invasion and metastasis both in vitro and in vivo using breast cancer models. Through RNA- and ChIP-sequencing, we identified IL11 as a direct transcriptional target of MAFF that mediates the invasive and metastatic behaviour of tumour cells. Since breast cancers express low levels of NRF2, which is a well-known binding partner of MAFF that regulates cellular antioxidant responses, we used mass spectrometry to determine MAFF binding partners and found that BACH1 was the most abundant MAFF binding partner of MAFF in our breast cancer models. Expanding this study to ovarian and lung cancer models, we also confirmed that MAFF enhances tumour invasion and metastasis, indicating its important role in a variety of tumour types.

In breast cancer patient tissues, MAFF expression (brown staining) is detected, and its intensity increases in more metastatic and aggressive tumours.

We further expand our studies to evaluate the role of MAFF in response to radiation. Specifically, we aim to investigate the role of MAFF in ferroptosis, a non-apoptotic cell death depending on iron and lipid peroxides that can contribute to radiation-induced cell death.

In collaboration with Dr Kristoffer Petersson, we also investigate the underlying biological mechanism of FLASH radiation, a novel ultra-high dose rate radiotherapy. By focusing on FLASH radiotherapy and MAFF-mediated redox pathways, we will provide a new insight in how transcriptional regulation leads to physiological changes in tumour, which might affect treatment outcomes.

IMPACT:

While ferroptosis has been identified as a novel pathway of radiation-induced cell death, the key regulator of this pathway still needs to be determined. Our programme will determine how MAFF regulates radiation-induced ferroptosis, which will enable us to identify novel and effective molecular target to enhance radiation responses. Investigation of FLASH effect on normal tissue protection will further help to develop novel strategies to current radiation treatment to increase tumour responses while protecting normal tissues.

REFERENCES:

• Vilaplana-Lopera N, Besh M, Moon EJ* (2021). Targeting Hypoxia: Revival of Old Remedies. Biomolecules. 11(11), 1604. *Corresponding author.
• Moon EJ**, Petersson K**, Olcina MM** (2021). The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT. International Journal of Radiation Biology. **Authors equally contributed. Co-corresponding author.
• Moon EJ, Mello SS, Li CG, Chi JT, Thakkar K, Kirkland JG,Lagory EL, Lee IJ, Diep AN, Miao Y, Rafat M, Vilalta M, Castellini L, Krieg AJ, Graves EE, Attard LD, Giaccia AJ (2021). The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature Communications. 12, 4308.
• Moon EJ, Giaccia AJ (2014). The dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radical Biology of Medicine. 79: 292-299.
• Klasson TD, LaGory EL, Zhao H, Huynh SK, Papandreou I, Moon EJ, Giaccia AJ (2022). ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma. Cancer and Metabolism, 10 (14).
• Mehibel M, Xu Y, Li CG, Moon EJ, Thakkar KN, Diep AN, Kim RK, Bloomstein JD, Xiao Y, Bacal J, Saldivar JC, Le QT, Cimprich KA, Rankin EB, Giaccia AJ (2021). Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination–deficient cancer models. The Journal of Clinical Investigation, 131(11): e146256.