Epigenetic Signature of Radioresistant Esophageal Carcinoma

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Epigenetic Signature of Radioresistant Esophageal Carcinoma

Segunda, 18.01.2021

Researchers from two Groups of Research Center IPO Porto Cancer: Biology & Epigenetics Group and Medical Physics, Radiobiology and Radiological Protection, recently published a study in the international journal Cell Death & Disease entitled: “JmjC-KDMs KMD3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma. This work highlights the role of lysine demethylases (KDMs), in particular KDM3A, in radioresistant behavior of esophageal squamous cell carcinoma cells, under hypoxia. The use of KDMs activity inhibitors concomitantly with radiation therapy significantly radiosensitized tumors through impaired DNA repair mechanisms, affecting both double strand breaks DNA damage pathways, namely homologous recombination and non-homologous end-joining. In particular, KDM3A knockdown, using CRISPR/cas9 techniques, and, consequently, the increment of demethylated lysine 9 histone 3 levels, a specific target of KDM3A activity, demonstrated a critical role in response to radiotherapy on Kyse-410 cell line, under hypoxic conditions. Overall, the results indicate that hypoxia induces KDM3A overexpression, conferring resistance to radiotherapy.

 

Authors and e Afilliations:

Catarina Macedo-Silva - Cancer Biology & Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Vera Miranda-Gonçalves - Cancer Biology & Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Ana Lameirinhas - Cancer Biology & Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Joana Lencart - Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Alexandre Pereira - Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

João Lobo - Cancer Biology & Epigenetics Group – Research Center and Department of Pathology, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP); Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), Porto, Portugal.

Rita Guimarães - Department of Pathology, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Ana Teresa Martins - Department of Pathology, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Rui Henrique - Cancer Biology & Epigenetics Group – Research Center and Department of Pathology, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP); Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), Porto, Portugal.

Isabel Bravo - Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP).

Carmen Jerónimo - Cancer Biology & Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto, Portugal, (CI-IPOP); Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), Porto, Portugal.

 

Abstract:

Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3Aknockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients’ survival.

 

Journal: Cell Death & Disease – Nature

 

Link: https://www.nature.com/articles/s41419-020-03279-y