SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells

Abstract

The Janus tyrosine kinases JAK1-3 and tyrosine kinase-2 (TYK2) are frequently hyperactivated in tumors. In lung cancers JAK1 and JAK2 induce oncogenic signaling through STAT3. A putative role of TYK2 in these tumors has not been reported. Here, we show a previously not recognized TYK2-STAT3 signaling node in lung cancer cells. We reveal that the E3 ubiquitin ligase seven-in-absentia-2 (SIAH2) accelerates the proteasomal degradation of TYK2. This mechanism consequently suppresses the activation of STAT3. In agreement with these data the analysis of primary non-small-cell lung cancer (NSCLC) samples from three patient cohorts revealed that compared to lung adenocarcinoma (ADC), lung squamous cell carcinoma (SCC) show significantly higher levels of SIAH2 and reduced STAT3 phosphorylation levels. Thus, SIAH2 is a novel molecular marker for SCC. We further demonstrate that an activation of the oncologically relevant transcription factor p53 in lung cancer cells induces SIAH2, depletes TYK2, and abrogates the tyrosine phosphorylation of STAT1 and STAT3. This mechanism appears to be different from the inhibition of phosphorylated JAKs through the suppressor of cytokine signaling (SOCS) proteins. Our study may help to identify molecular mechanisms affecting lung carcinogenesis and potential therapeutic targets.

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

“…It should be highlighted that the previous study did not use any prior stimulation with IFNβ, which could potentially contribute to the observed differences between the two screens. The ubiquitin ligase SIAH, identified in our study as a negative regulator, was previously shown to degrade TYK225. The re-identification of previously known regulators of IFN-I signaling SIAH2 and TRIM9 in our screen confirm that the approach we undertook was reliable.…”

Overexpression of Siah2 Is Associated With Poor Prognosis in Patients With Epithelial Ovarian Carcinoma

“…The protein expression of Siah2 reportedly correlates with clinicopathologic factors and poor prognosis in various cancers, such as breast cancer, 11,12 prostate cancer, 13,14 lung cancer, 15,16 pancreatic cancer, 17 liver cancer, 18 oral cancer, 19 and melanoma. 20,21 However, the role of Siah2 expression in gynecological cancers remains unclear.…”

“…Moreover, Siah2 has been described as a proto-oncogene. 7,10 Increasing evidence revealed that Siah2 promotes the progression of various malignant tumors, such as breast cancer, 11,12 prostate cancer, 13,14 lung cancer, 15,16 pancreatic cancer, 17 liver cancer, 18 oral cancer, 19 and melanoma. 20,21 However, the prognostic value of Siah2 expression in EOC remains unknown.…”

The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers

“…The expression of SIAH2 can increase due to gene copy number duplications in the more aggressive TNBC type [33]. This mechanism has also been suggested for lung squamous cell carcinomas [11]. In Japanese hormone-receptor-positive (HRP) female breast cancer patients (1086 patients and 1816 female controls), a significant association of the disease with an intronic SNP in SIAH2 was reported [65].…”

“…While both, SIAH1 and SIAH2 are inducible by the tumor suppressor and transcription factor p53, sex hormones and cytokine signaling only contribute to the regulation of SIAH2 [10][11][12][13][14][15][16][17] (Fig. 1; please note: details are discussed in Section 3).…”