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Autophagy. 2016 Nov;12(11):2167-2182. Epub 2016 Aug 25.

ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2.

Author information

  • 1a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
  • 2b Institute of Combined Injury, State Key Labortory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, The Third Military Medical University , Chongqing , China.
  • 3c Institute of Immunology, The Third Military Medical University , Chongqing , China.
  • 4d Biomedical Analysis Center, Third Military Medical University , Chongqing , China.

Abstract

Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.

KEYWORDS:

ABHD5; autophagy; colorectal cancer; genome instability; tumorigenesis

PMID:
27559856
PMCID:
PMC5103361
[Available on 2017-08-25]
DOI:
10.1080/15548627.2016.1217380
[PubMed - in process]
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