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Aberrant SPOP-CHAF1A ubiquitination axis triggers tumor autophagy that endows a therapeutical vulnerability in

Wei Yan1, Xue Shi1, Huihan Wang1

  • 1Department of Hematology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, Liaoning, China.

Journal of Translational Medicine
|June 30, 2022
PubMed
Abstract

Insights

Aberrant epigenetic changes drive cancer. This study reveals the SPOP/CHAF1A axis modulates autophagy in Diffuse large B-cell lymphoma (DLBCL), identifying TFEB as a key regulator and potential therapeutic target.

Area of Science:

  • Epigenetics and Cancer Biology
  • Tumorigenesis and Autophagy Regulation
  • Lymphoma Pathogenesis

Background:

  • Aberrant epigenetic modifications, including DNA methylation and histone alterations, are implicated in metabolic disorders and cancer.
  • Diffuse large B-cell lymphoma (DLBCL) pathogenesis involves complex molecular events, including epigenetic dysregulation.
  • Autophagy plays a critical role in tumor development and progression, and its modulation is a key area of cancer research.

Purpose of the Study:

  • To investigate the biological roles of the SPOP/CHAF1A epigenetic axis in modulating tumor autophagy during DLBCL tumorigenesis.
  • To elucidate the molecular mechanisms by which SPOP and CHAF1A interact to influence DLBCL progression.
  • To identify potential therapeutic targets based on the understanding of the SPOP/CHAF1A/TFEB signaling pathway in DLBCL.

Main Methods:

  • Utilized immunohistochemistry (IHC) and The Cancer Genome Atlas (TCGA) data to assess CHAF1A expression in DLBCL.
  • Performed bioinformatic analyses, including differential expression, functional enrichment, and survival analyses.
  • Conducted in vitro (colony formation, Transwell, CCK-8) and in vivo (xenograft models) assays to evaluate cellular aggressiveness and tumor growth.
  • Employed ubiquitination, Chromatin immunoprecipitation (ChIP-qPCR), and Western blotting to investigate SPOP-CHAF1A interactions and epigenetic regulation of TFEB.

Main Results:

  • CHAF1A was found to be highly expressed in DLBCL, correlating with inferior patient prognosis and enhanced tumor aggressiveness (proliferation, migration, growth).
  • The E3 ubiquitin ligase SPOP targets CHAF1A for degradation; SPOP deficiency in DLBCL leads to CHAF1A accumulation, promoting malignant phenotypes.
  • CHAF1A directly binds to and activates TFEB, enhancing its transcriptional activity and downstream targets, thereby modulating lysosomal biogenesis and autophagy.
  • TFEB inhibition effectively suppressed the growth of SPOP-deficient DLBCL in vivo models.

Conclusions:

  • Aberrantly elevated CHAF1A in SPOP-deficient DLBCL is a key driver of tumorigenesis.
  • The SPOP/CHAF1A/TFEB axis represents a critical regulatory pathway influencing autophagy and DLBCL progression.
  • Targeting this axis, particularly TFEB, offers a promising therapeutic strategy for DLBCL treatment.
Keywords:
AutophagyCHAF1ADLBCLSPOPUbiquitination

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