DFNA5 inhibits colorectal cancer proliferation by suppressing the mTORC1/2 signaling pathways via upregulation of DEPTOR

Cell Cycle. 2022 Oct;21(20):2165-2178. doi: 10.1080/15384101.2022.2088570. Epub 2022 Aug 3.

Abstract

The human deafness, autosomal dominant 5 gene (DFNA5), a newly discovered executor of pyroptosis, has been strongly implicated in the tumorigenesis of several human cancers. However, an understanding of the functional role of DFNA5 in the development and progression of colorectal cancer (CRC) is limited. In this study, we demonstrated that DFNA5 was downregulated in CRC tissues. Ectopic expression of DFNA5 inhibited tumor cell growth in vitro, retarded tumor formation in vivo, and blocked a cell-cycle transition from the G0/G1 to the S phase, whereas a DFNA5 knockdown promoted cell proliferation. Western blotting showed that the levels of cell cycle-related proteins, including cyclin D1, cyclin E, CDK2, and p21, were accordingly altered upon DFNA5 overexpression or DFNA5 knockdown. Mechanistic studies indicated that DFNA5 exerted its tumor suppressor functions by antagonizing mTORC1/2 signaling via upregulation of DEPTOR. In addition, blockage of mTORC1/2 signaling by Torin-1 abolished the accelerative proliferation by DFNA5 knockdown. In conclusion, these results indicated that DFNA5 inhibits the proliferation and tumor formation of colon cancer cells by suppressing mTORC1/2 signaling.

Keywords: DEPTOR; DFNA5; cell cycle; colorectal cancer; mTORC1/2; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Colonic Neoplasms* / pathology
  • Colorectal Neoplasms* / pathology
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • Gene Expression Regulation, Neoplastic
  • Hearing Loss, Sensorineural
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Pore Forming Cytotoxic Proteins
  • Signal Transduction
  • Up-Regulation / genetics

Substances

  • Cyclin E
  • GSDME protein, human
  • Intracellular Signaling Peptides and Proteins
  • Pore Forming Cytotoxic Proteins
  • Cyclin D1
  • DEPTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1

Supplementary concepts

  • Deafness, Autosomal Dominant 5

Grants and funding

This work was funded by a grant from the National Natural Science Foundation of China [Grant Serial Numbers: 81972720, 81101874, 81172362], The Coordinative and Innovative Plan Projects of the Science and Technology Program in Shaanxi Province [Grant Serial Number: 2013KTCQ03-08], the Fundamental Research Funds for the Central Universities [Grant Serial Number: xjj2018123], and The institutional foundation of the first affiliated hospital of Xi’an Jiaotong University [Grant Serial Number: 2019QN-12]