In vitro evidence of NLRP3 inflammasome regulation by histone demethylase LSD2 in renal cancer: a pilot study
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In vitro evidence of NLRP3 inflammasome regulation by histone demethylase LSD2 in renal cancer: a pilot study Aman Kumar1,2 · Nayudu Nallabelli2 · Ujjawal Sharma1 · Niti Kumari1 · Shrawan Kumar Singh3 · Nandita Kakkar4 · Rajendra Prasad1 Received: 1 May 2020 / Accepted: 26 July 2020 © Springer Nature B.V. 2020
Abstract NLRP3 pathway plays a vital role in the pathogenesis of different human cancers but still the regulation of NLRP3 pathway largely unknown. Therefore, we examined the levels of NLRP3 and its downstream components (caspase-1 and IL-1β) and its relationship with histone modifiers in renal cancer pathogenesis. Total 30 cases of clear cell renal cell carcinoma (ccRCC), were studied for NLRP3, caspase-1 and IL-1β expression using real-time PCR, which showed the augmented levels of all the three components of NLRP3 inflammasome pathway in ccRCC. Next, role of the FAD dependent monoamine oxidases (LSD2) and jumonji C (JmjC)-domain-containing, iron-dependent dioxygenases (KDM5A) histone demethylases were evaluated in regulation of NLRP3 inflammasome pathway in-vitro using RCC cell line. It was observed that silencing of KDM5A didn’t alter the levels of neither of the NLRP3 component but inhibition of LSD2 showed significant effect on NLRP3 expression while no change in caspase-1 and IL-1β levels. This study suggests that rather LSD2 not KDM5A lysine demethylase family might be involved in the regulation of NLRP3 inflammasome in cancer cells which could be useful for deciphering the future therapeutic targets for the disease. Keywords NLRP3 · LSD2 · KDM5A · Inflammasome · Epigenetics · Histone modifiers
Background Tumor microenvironment contributes to the promotion of tumor growth, migration, invasion, and angiogenesis as a result of inflammation. Inflammasomes, one of the arms of innate immune system, is triggered by various pathogen associated molecular patterns (PAMPs) and cellderived damage associated molecular patterns (DAMPs). Nucleotide-binding oligomerization domain (NOD), C-terminal leucine-rich repeat (LRR) domain and pyrin * Rajendra Prasad [email protected] 1
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
2
Department of Ophthalmology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3
Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
domain-containing protein 3 (NLRP3) is the well-studied inflammasome, which ultimately leads to the activation of effector cytokines; Interleukins (ILs): IL-1β and IL-18 that plays a crucial role in carcinogenesis [1]. Activation of NLRP3 mediated inflammasome has been observed in various cancers such as colorectal cancer, gastric cancer, prostate cancer, etc. along with its therapeutic potential in lung cancer as well as in pancreatic cancer [2]. Although the different studies indi
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