PJA2 suppresses colorectal cancer progression by controlling HDAC2 degradation and stability.

Abstract

Abstract Background The Praja Ring Finger Ubiquitin Ligase 2 (PJA2), one of the RING ligase family, has been reported to be degrading differential substrates and regulating diverse diseases. However, the E3 ligase function of PJA2 played in cancer development and progression, especially in colorectal cancer, is still almost unknown. Methods The correlation between PJA2 and clinical characteristics was explored through the TCGA and GEO data sets. The qRT-PCR and Immunohistochemical assays were employed to assess the expression of PJA2 in CRC tissues and cell lines. The biological functions of PJA2 were verified by cell counting kit-8, colony formation, flow cytometry, cell-derived xenograft, AOM/DSS colorectal tumorigenesis model and other in vivo and in vitro experiments. The RNA-seq, mass spectrometry analysis, GST pull-down, Chromatin Immunoprecipitation and Immunofluorescence were utilized to disclose the underlying molecular mechanisms of PJA2 in CRC proliferation and apoptosis. Results Our research discovered that PJA2 was abnormally downregulated in CRC tissues and cell lines, and the lower expression of PJA2 was detected, the poorer prognosis was present. Functionally, further in vivo and in vitro experiments jointly uncovered that PJA2 acted as a tumor suppressor gene via inhibiting tumor proliferation and promoting cancer cell apoptosis in CRC progression. Regarding mechanism, PJA2 could recognize HDAC2 through the RBD domain and bind with the N-terminal of HDAC2 to ubiquitinate and degrade HDAC2 at K90 residue. PJA2-mediated ubiquitination and degradation of HDAC2 could counteract the transcriptional suppression of the IFIT family and PJA2, thus facilitating the transcription of the IFIT family to promote cancer cell apoptosis and inhibit tumor proliferation. Conclusion Our data showed that PJA2 interacted with HDAC2, promoted the poly-ubiquitination and degradation of HDAC2, abrogated the transcriptional suppression of the IFIT family and PJA2, constituted a positive feedback loop, and prevented tumor proliferation. Hence, PJA2 might be a potential therapeutic target for CRC, and interruption of this positive feedback loop would be a treatment strategy to slow or restrain the progression of CRC.