Signal Transduction and Targeted Therapy (Jun 2022)

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

  • Yalan Lu,
  • Rong Huang,
  • Jianming Ying,
  • Xingchen Li,
  • Tao Jiao,
  • Lei Guo,
  • Haitao Zhou,
  • Han Wang,
  • Amannisa Tuersuntuoheti,
  • Jianmei Liu,
  • Qichen Chen,
  • Yanhong Wang,
  • Luying Su,
  • Changyuan Guo,
  • Fu Xu,
  • Ziyi Wang,
  • Yan Lu,
  • Kai Li,
  • Junbo Liang,
  • Zhen Huang,
  • Xiao Chen,
  • Jinjie Yao,
  • Hanjie Hu,
  • Xiaowen Cheng,
  • Yufeng Wan,
  • Xinyan Chen,
  • Ning Zhang,
  • Shiying Miao,
  • Jianqiang Cai,
  • Linfang Wang,
  • Changzheng Liu,
  • Wei Song,
  • Hong Zhao

Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13


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Abstract Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.