Mitochondria chaperone-mediated stability of SIX1 opens a door for prostate cancer progression and castration resistance
This work shows how mitochondria chaperone GRP75 regulates the stability of SIX1, a transcription factor for embryonic development and cancer progression. Our findings provide important insights into the protein degradation mechanism as well as a novel avenue for prostate cancer therapy.
We have been devoting to the filed of protein degradation & cancer therapy for many years. The most important research project of our team is to identify the co-regulators on modification and degradation of key oncoproteins or players that drive cancer development and progression. Identification of these co-regulators will conceivably help us understand the underlying mechanisms of protein degradation and develop novel strategies to trigger oncoprotein degradation for winning the battle against cancer.
Prostate cancer (PC) is a common cancer with increasing cases and deaths in males. Over the past decades, androgen receptor (AR) has been proposed as the most significant target for PC therapy because AR inhibitors can greatly improve the prognosis of most PC patients in clinical applications. Recently, we have also been identified ubiquitin specific peptidase 14 (USP14), a proteasomal deubiquitinating enzyme, as an oncogenic partner of AR in driving the progression of PC and AR positive breast cancer[1, 2]. However, there are 20%-40% of PC patients do not respond to the AR-targeted therapy, or even develop metastatic castration-resistant PC (CRPC), which is considered as the most dangerous PC with extremely limited treatment option. Thus, alternative targets that may cover more PC patients or overcome CRPC are urgently needed.
Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that mainly promotes cellular proliferation in embryo. Although the activated SIX1 signal is turned off after the embryo develops, aberrant expression and reactivation of SIX1 were observed in PC. More importantly, high expression of SIX1 predicts poor prognosis in various cancers[4, 5]. We therefore wondered what mechanism contributes to the high expression level of SIX1.
Heat shock protein (HSP) family is the main category of molecular chaperones and plays an important role in various biological processes, including protein folding, assembly, transport, and degradation[6, 7]. We wondered whether mitochondrial HSP regulated protein degradation or protein level of SIX1 in PC cells. Using Co-IP and mass spectrometry (IP-MS), we unexpectedly found that glucose regulated protein 75 (GRP75) was a mitochondrial chaperone of SIX1. We showed that the knockdown of GRP75 reduced expression of SIX1. This effect results from the posttranscriptional level, but not transcriptional level.
Mechanistically, we revealed that GRP75 provides a molecular platform to recruit the deubiquitinating enzyme ubiquitin specific peptidase 1 (USP1) to suppress Lys48-linked polyubiquitination of SIX1. The formation of GRP75-USP1-SIX1 complex is critical to SIX1 stability and is required for the proliferation and castration resistance of PC. Furthermore, GRP75-USP1 was positively correlated with the protein level of SIX1 in our clinical observations. These findings not only unravel a novel mechanism on protein degradation, but also provide a potential anti-tumor strategy against PC.
Figure 1. A molecular model of the GRP75-USP1-SIX1 complex in prostate cancer.
The original article is available in https://www.nature.com/articles/s41388-021-01851-0
The major members of our Team in Lab for protein modification and degradation
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 Y. Liao, X. Xia, N. Liu, J. Cai, Z. Guo, Y. Li, L. Jiang, Q.P. Dou, D. Tang, H. Huang, J. Liu, Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination, Oncogene, 37 (2018) 1896-1910.
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 J. Zeng, R. Shi, C.X. Cai, X.R. Liu, Y.B. Song, M. Wei, W.L. Ma, Increased expression of Six1 correlates with progression and prognosis of prostate cancer, Cancer cell international, 15 (2015) 63.
 H. Burress, A. Kellner, J. Guyette, S.A. Tatulian, K. Teter, HSC70 and HSP90 chaperones perform complementary roles in translocation of the cholera toxin A1 subunit from the endoplasmic reticulum to the cytosol, The Journal of biological chemistry, 294 (2019) 12122-12131.
 Y. Liao, Y. Liu, X. Xia, Z. Shao, C. Huang, J. He, L. Jiang, D. Tang, J. Liu, H. Huang, Targeting GRP78-dependent AR-V7 protein degradation overcomes castration-resistance in prostate cancer therapy, Theranostics, 10 (2020) 3366-3381.