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DNA damage-inducible transcript 4 is an innate guardian for human squamous cell carcinoma and an molecular vector for

Xiaojiao Zhang1, Fuling Luo2, Jing Li3

  • 1Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Experimental Dermatology
|October 30, 2018
PubMed

Insights

DNA damage-inducible transcript 4 (DDIT4) is suppressed in skin cancer, hindering autophagy and promoting proliferation. Vitamin D enhances DDIT4, inhibiting cancer growth via the mTORC1 pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Cutaneous squamous cell carcinoma (SCC) is a prevalent non-melanoma skin cancer with limited therapeutic options.
  • The precise mechanisms of SCC tumorigenesis and effective treatments remain incompletely understood.

Purpose of the Study:

  • To investigate the role of DNA damage-inducible transcript 4 (DDIT4) in human SCC.
  • To elucidate the molecular mechanisms underlying 1,25(OH)2D3's anti-carcinoma effects in SCC.

Main Methods:

  • Analysis of DDIT4 expression in human SCC tissues and cell lines.
  • Investigation of DDIT4's impact on keratinocyte proliferation and autophagy via the mTORC1 pathway.
  • Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) to verify VDR-DDIT4 complex formation.
  • In vivo studies using xenograft tumor-bearing mice models treated with 1,25(OH)2D3.
  • Assessment of DDIT4 expression in actinic keratoses and UV-irradiated mouse skin.

Main Results:

  • DDIT4 is significantly suppressed in human SCC, correlating with accelerated keratinocyte proliferation and impaired autophagy.
  • 1,25(OH)2D3 enhances DDIT4 expression, activates autophagy, and inhibits the mTORC1 pathway, leading to anti-proliferative effects.
  • A direct VDR-DDIT4 transcription complex was identified, explaining 1,25(OH)2D3's transcriptional regulation of DDIT4.
  • In vivo studies confirmed the anti-carcinoma efficacy of 1,25(OH)2D3, with DDIT4 mediating its effects through mTORC1.
  • Elevated DDIT4 was observed in actinic keratoses, and UV irradiation paradoxically increased epidermal DDIT4 expression.

Conclusions:

  • DDIT4 plays a critical role in SCC development by regulating keratinocyte proliferation and autophagy.
  • 1,25(OH)2D3 exerts anti-cancer effects in SCC by upregulating DDIT4 expression and modulating the mTORC1 pathway.
  • UV irradiation exhibits a dual role, potentially promoting SCC carcinogenesis while inducing protective DDIT4 expression in early stages.
Keywords:
125-dihydroxyvitamin D3DNA damage-inducible transcript 4mammalian target of rapamycinsquamous cell carcinomaultraviolet

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