2. Academic Validation
  3. BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis

BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis

  • Adv Sci (Weinh). 2024 Mar;11(11):e2304263. doi: 10.1002/advs.202304263.
Haiyan Wang 1 2 3,  Long Shu 1 3,  Cairui Lv 1 3,  Na Liu 1 3,  Yao Long 1 3,  Xintong Peng 1 3,  Huli Ling 1 3,  Tania Tao 1 4,  Jun Tang 1 3,  Yan Cheng 5,  Shuang Liu 6,  Desheng Xiao 7,  Yongguang Tao 1 3 4 8
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University, Ministry of Education), Department of Pathology, Xiangya Hospital, Central South University, Hunan, 410078, China.
  • 2 Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
  • 3 NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
  • 4 Hunan Key Laboratory of Early Diagnosis and Precision Therapy, Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 5 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 6 Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 7 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 8 Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410031, China.
PMID: 38178583 DOI: 10.1002/advs.202304263
Abstract

Various forms of programmed cell death (PCD) exhibit distinct characteristics depending on their specific molecular mechanisms, and there are interactions among these different forms. Ferroptosis, which is related to Autophagy and Apoptosis, has an unknown potential interaction with Pyroptosis. This study revealed a mutually antagonistic relationship between Ferroptosis and Pyroptosis, with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) playing a key role in their interaction. It is found that HMGCR predominantly localized to mitochondria during Ferroptosis but shifted to the endoplasmic reticulum following treatment with a Pyroptosis Inducer. Furthermore, this study demonstrated that BRCC36 (BRCA1/BRCA2-containing complex subunit 36) deubiquitinated HMGCR in a manner dependent on deubiquitinating enzyme (DUB) activity, and inhibited Ferroptosis and promoted Pyroptosis. Moreover, as an oncogene in hepatocellular carcinoma (HCC), BRCC36 promoted Cancer cell proliferation, migration, invasion, and tumor growth. Thiolutin, an inhibitor of BRCC36, effectively suppressed the interaction between BRCC36 and HMGCR, leading to the inhibition of HCC growth. Therefore, targeting BRCC36 can offer a novel and promising therapeutic strategy for HCC treatment. In conclusion, these findings provide new theoretical evidence for further characterizing tumor heterogeneity and offer new molecular targets for the diagnosis and treatment of HCC.

Keywords

BRCC36; HMGCR; endoplasmic reticulum; ferroptosis; mitochondria; pyroptosis.

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