Aberrant Expression of X-Linked Genes <i>RbAp46, Rsk4</i>, and <i>Cldn2</i> in Breast Cancer

Thakur, Archana; Rahman, KM Wahidur; Wu, Jack; Bollig, Aliccia; Biliran, Hector; Lin, Xiukun; Nassar, Hind; Grignon, David J.; Sarkar, Fazlul H.; Liao, Joshua D.

doi:10.1158/1541-7786.mcr-06-0071

Cited by 75 publications

(63 citation statements)

References 27 publications

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“…RSK4 has previously been characterized as essential for p53-dependent proliferation arrest as well as stress-and oncogene-induced senescence (28,58,59). Interestingly, the RSK4 isoform exhibits constitutively high activity, is upregulated in MMTV-Myc mouse breast tumors, is aberrantly expressed in breast cancer, and has been implicated in sunitinib resistance (58,(60)(61)(62)(63). Here, we demonstrate that RSK3 and RSK4 can also mediate resistance to PI3K inhibitors in breast cancer cells both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 62%

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Serra¹,

Eichhorn²,

García-García³

et al. 2013

J. Clin. Invest.

116

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The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK-or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.

show abstract

Section: Discussionmentioning

confidence: 62%

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Serra¹,

Eichhorn²,

García-García³

et al. 2013

J. Clin. Invest.

116

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“…The above results suggest that RSK4 can inhibit cell proliferation. Thakur et al (19) revealed higher expression of RSK4 was found in normal mammary ductals, and low expression or no expression of RSK4 in benign breast lesions (papilloma). RSK4 is likely to have a role in the development or progression of human breast cancer.…”

Section: Discussionmentioning

confidence: 99%

RSK4 knockdown promotes proliferation, migration and metastasis of human breast adenocarcinoma cells

Zhu

Liu

et al. 2015

Oncology Reports

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Abstract. RSK4 has been shown to inhibit the growth of certain cancer cells. The aim of this study was to construct a lentiviral vector of RSK4-shRNA (Lenti-RSK4-shRNA) to specifically block the expression of RSK4 in the human breast adenocarcinoma cell line MCF-7, and investigate the effect of the RSK4 gene on cell proliferation and invasion in vitro and in vivo. Lenti-RSK4-shRNA was stably transfected into MCF-7 cells. RSK4 mRNA and protein expression were measured by fluorescence quantitative RT-PCR and western blot analysis. Cell proliferation was evaluated by MTT assays and flow cytometric analysis. Invasion was evaluated by Transwell assays and xenograft nude mouse models. The expression of RSK4 mRNA, Ki-67 mRNA, cyclin D1 mRNA, CXCR4 mRNA and E-cadherin mRNA of tumor xenografts were detected by fluorescence quantitative RT-PCR. Significant decreases in RSK4 mRNA and protein expression was detected in MCF-7 cells carrying lentiviral RSK4-shRNA vector. The cell proliferation was significantly promoted in the RSK4-shRNA group as compared to that in the negative and blank control group. In addition, the number of cells in the S phase in the RSK4-shRNA group was significantly greater than the blank and negative control groups (P<0.05). Furthermore, the number of invading cells was increased in the RSK4-shRNA (P<0.05). In vivo, we also found that the knockdown of RSK4 promoted tumorigenicity and migration in the xenograft nude mouse model. In addition, we showed that the RSK4 mRNA and E-cadherin mRNA expression were significantly lower in the RSK4-shRNA group compared to that in negative and blank control group (both P<0.05), while the Ki-67 mRNA, cyclin D1 mRNA and CXCR4 mRNA were higher in the shRNA group compared to that in negative and blank control group (both P<0.05). In conclusion, downregulation of RSK4 expression is indicated to be associated with tumor cell proliferation and invasion, and silencing of the RSK4 may be involved in the development and progression of breast cancer through the changes of Ki-67, cyclin D1, CXCR4 and E-cadherin, and suggesting that RSK4 may act as a potential cancer suppressor gene and therapeutic target for the treatment of breast cancer.

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“…For example, aberrant RSK activation contributes to multiple malignant conditions, including various breast and ovarian cancers and myeloma (47)(48)(49)(50). Additionally, inactivating mutations in the RSK2-encoding gene are responsible for Coffin-Lowry syndrome, which is characterized by severe mental retardation and progressive skeletal deformations (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus ORF45 Mediates Transcriptional Activation of the HIV-1 Long Terminal Repeat via RSK2

Karijolich

Zhao

Peterson

et al. 2014

J Virol

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Robust activation of human immunodeficiency virus type 1 (HIV-1) gene expression occurs upon superinfection with Kaposi's sarcoma-associated herpesvirus (KSHV), a common AIDS-associated pathogen. Though the mechanisms underlying this phenotype remain unknown, several KSHV-encoded factors have been reported to stimulate HIV-1 long terminal repeat (LTR) activity. Here, we systematically evaluated the ability of KSHV tegument proteins to modulate the activation of an integrated HIV-1 LTR and revealed that the most potent individual activator is ORF45. ORF45 directs an increase in RNA polymerase II recruitment to the HIV-1 LTR, leading to enhanced transcriptional output. ORF45 is a robust activator of the p90 ribosomal S6 kinases (RSK), and we found that this activity is necessary but not sufficient to increase transcription from the LTR. Of the three widely expressed RSK isoforms, RSK2 appears to be selectively involved in LTR stimulation by both KSHV ORF45 and HIV-1 Tat. However, constitutively active RSK2 is unable to stimulate the LTR, suggesting that ORF45 may preferentially direct this kinase to a specific set of targets. Collectively, our findings reveal a novel transcriptional activation function for KSHV ORF45 and highlight the importance of RSK2 in shaping the transcriptional environment during infection. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is a prominent AIDS-associated pathogen. Previous studies have shown that infection of cells containing human immunodeficiency virus type 1 (HIV-1) with KSHV leads to potent stimulation of HIV-1 gene expression by activating the HIV-1 promoter, termed the long terminal repeat (LTR).Here, we compared the abilities of various KSHV proteins to activate gene expression from the HIV-1 LTR and found that KSHV ORF45 is the most potent activator. ORF45 is known to induce cell signaling through ribosomal S6 kinase (RSK) and enhance protein translation. However, we revealed that the activation of a specific isoform of RSK by ORF45 also leads to increased mRNA synthesis from the LTR by the host RNA polymerase. Collectively, our findings provide new insight into the interviral interactions between KSHV and HIV that may ultimately impact disease.

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Aberrant Expression of X-Linked Genes RbAp46, Rsk4, and Cldn2 in Breast Cancer

Cited by 75 publications

References 27 publications

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

RSK4 knockdown promotes proliferation, migration and metastasis of human breast adenocarcinoma cells

Kaposi's Sarcoma-Associated Herpesvirus ORF45 Mediates Transcriptional Activation of the HIV-1 Long Terminal Repeat via RSK2

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