Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3

Cancer Lett. 2022 Feb 28:527:127-139. doi: 10.1016/j.canlet.2021.12.017. Epub 2021 Dec 17.

Abstract

Colorectal cancers (CRCs) with the BRAF V600E mutation exhibit upregulation of programmed death ligand 1 (PD-L1) but fail to respond to immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. Recent studies have explored the intracellular functions of PD-L1. Here, we demonstrate that PD-L1 was highly expressed in both the cytoplasm and nucleus of BRAF-mutated CRC tumor cells and tissues. Nuclear PD-L1 (nPD-L1) promoted the growth of tumor cells both in vitro and in vivo. Mechanistic investigations revealed that PD-L1 translocation into the nucleus was facilitated by the binding of p-ERK. Further, nPD-L1 upregulated the expression of cell cycle regulator BUB1 via interactions with thyroid hormone receptor-associated protein 3 (THRAP3), thereby accelerating cell cycle progression and promoting cell proliferation. Moreover, BRAF V600E-mutated CRC cells exhibited upregulation of PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1, which promotes cell cycle progression in an immune-independent manner in BRAF V600E-mutated CRC. Our study provides novel insight into the mechanisms underlying BRAF V600E-mutated CRC progression.

Keywords: Colorectal cancer; Nuclear PD-L1; THRAP3; Tumor proliferation; p-ERK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism*
  • Cell Proliferation
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Humans
  • Immunotherapy / methods*
  • Mice
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • DNA-Binding Proteins
  • THRAP3 protein, human
  • Transcription Factors