Downregulation of protein kinase C gamma reduces epithelial property and enhances malignant phenotypes in colorectal cancer cells

Reiko Satow; Yudai Suzuki; Shinobu Asada; Sae Ota; Masashi Idogawa; Shiori Kubota; Noi Ikeo; Atsuko Yoneda; Kiyoko Fukami

doi:10.1016/j.isci.2022.105501

Downregulation of protein kinase C gamma reduces epithelial property and enhances malignant phenotypes in colorectal cancer cells

iScience. 2022 Nov 4;25(12):105501. doi: 10.1016/j.isci.2022.105501. eCollection 2022 Dec 22.

Authors

Reiko Satow¹, Yudai Suzuki¹, Shinobu Asada¹, Sae Ota¹, Masashi Idogawa², Shiori Kubota¹, Noi Ikeo¹, Atsuko Yoneda¹, Kiyoko Fukami¹

Affiliations

¹ Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan.
² Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Abstract

Loss of epithelial integrity is associated with colorectal cancer (CRC) aggressiveness. Protein kinase C (PKC) is frequently implicated in human cancers, but the role of PKCγ in CRC remains poorly understood. Here, we show that PKCγ, a conventional PKC, is expressed in normal colonic epithelium, but this is lower in dedifferentiated CRC. PKCγ expression was downregulated by SNAI1 overexpression, and low PKCγ expression was associated with poor prognosis in patients with CRC. Transient or stable knockdown of PKCγ reduced E-cadherin expression in CRC cells. PKCγ knockdown enhanced proliferation, anchorage-independent cell growth, resistance to anti-cancer drugs, and in vivo tumor growth of DLD-1 cells. We have also identified phosphorylation substrates for PKCγ. Among them, ARHGEF18, a RhoA activator that stabilizes cell-cell junctions, was phosphorylated and stabilized by PKCγ. Thus, these results suggest that the downregulation of PKCγ decreases the epithelial property of CRC cells and enhances its malignant phenotypes.

Keywords: Cancer; Molecular biology.