P21-activated kinase 5 potentiates the chemoresistant phenotype of liver cancer

Zhang, Dingguo; Gong, Chan‐Chan; Wu, Xiaojin; Ren, Xiubao; Sedaka, Randee; Chen, Weicong; Huo, Fu‐Chun; Chen, Cheng; Du, Wen‐Qi; Pei, Dong‐Sheng

doi:10.1038/s41392-020-00409-y

Cited by 6 publications

(4 citation statements)

References 5 publications

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“…The serine‐rich proteins piqued our interest in examining the phosphorylation regulation between SRSF11 and PAK5 kinase, the latter of which is a Ser/Thr protein kinase that has oncogenic functions in diverse types of cancer 51 . Because the previously described SRPK, CLK and topoisomerase 1 families all tended to phosphorylate serine sequences, 19 we concentrated on the serine‐rich RS domain.…”

Section: Discussionmentioning

confidence: 99%

“…The serine-rich proteins piqued our interest in examining the phosphorylation regulation between SRSF11 and PAK5 kinase, the latter of which is a Ser/Thr protein kinase that has oncogenic functions in diverse types of cancer. 51 Because the previously described SRPK, CLK and topoisomerase 1 families all tended to phosphorylate serine sequences, 19 we concentrated on the serine-rich RS domain. Given the lack of a specific antibody detecting the phosphorylated status of SRSF11, Phos-tag SDS-PAGE experiments were applied to differentiate the phosphorylated and unphosphorylated status of proteins by using a normal antibody.…”

Section: Discussionmentioning

confidence: 99%

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Alternative splicing of HSPA12A pre‐RNA by SRSF11 contributes to metastasis potential of colorectal cancer

Pan

Huo

Kang

et al. 2022

Clinical & Translational Med

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Background Dysregulation of alternative splicing (AS) induced by serine/arginine‐rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine‐rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown. Methods The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA‐seq technology was used to analyze and screen SRSF11‐triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini‐gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co‐IP) and Phospho‐tag SDS‐PAGE experiments were used to investigate PAK5‐mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction. Results In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro‐metastatic role in vitro and in vivo. By screening SRSF11‐regulated AS events, we identified the binding motif of SRSF11‐triggered splicing‐switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N‐cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation. Conclusions SRSF11 exerts pro‐metastatic effects in CRC by inhibiting the AS of HSPA12A pre‐RNA. Our findings point to SRSF11‐regulated HSPA12A splicing as a novel relationship between SRSF11‐regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alternative splicing of HSPA12A pre‐RNA by SRSF11 contributes to metastasis potential of colorectal cancer

Pan

Huo

Kang

et al. 2022

Clinical & Translational Med

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“…Cancer cells upregulate the drug transporters as a mechanism to combat drug resistance. PAK5 and ABCB1 are positively correlated in HCC patient samples [103]. In HCC, cells expressing high PAK7 are resistant to radiation and enhance radiosensitivity through increasing H2AX [104] In lung cancer cells, PAK5 interacts with Sox2 and phosphorylates Sox2.…”

Section: Pak5/7 In Drug Resistancementioning

confidence: 99%

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

et al. 2023

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Over the last three decades, p21-activated kinases (PAKs) have emerged as prominent intracellular nodular signaling molecules in cancer cells with a spectrum of cancer-promoting functions ranging from cell survival to anchorage-independent growth to cellular invasiveness. As PAK family members are widely overexpressed and/or hyperactivated in a variety of human tumors, over the years PAKs have also emerged as therapeutic targets, resulting in the development of clinically relevant PAK inhibitors. Over the last two decades, this has been a promising area of active investigation for several academic and pharmaceutical groups. Similar to other kinases, blocking the activity of one PAK family member leads to compensatory activity on the part of other family members. Because PAKs are also activated by stress-causing anticancer drugs, PAKs are components in the rewiring of survival pathways in the action of several therapeutic agents; in turn, they contribute to the development of therapeutic resistance. This, in turn, creates an opportunity to co-target the PAKs to achieve a superior anticancer cellular effect. Here we discuss the role of PAKs and their effector pathways in the modulation of cellular susceptibility to cancer therapeutic agents and therapeutic resistance.

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“…The leading causes of the HCC with high incidence include chronic hepatitis B virus infections (HBV), hepatitis C virus (HCV) infections, and food intake contaminated with aflatoxin B (Fig. 1C) [6][7][8][9]. Other risk factors include chemical carcinogens exposure, obesity, diabetes, and alcohol abuse (Fig.…”

Section: Current Epidemiology Of Hccmentioning

confidence: 99%

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

et al. 2021

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies.

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P21-activated kinase 5 potentiates the chemoresistant phenotype of liver cancer

Cited by 6 publications

References 5 publications

Alternative splicing of HSPA12A pre‐RNA by SRSF11 contributes to metastasis potential of colorectal cancer

Alternative splicing of HSPA12A pre‐RNA by SRSF11 contributes to metastasis potential of colorectal cancer

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

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