# KHDRBS1

## Overview
KHDRBS1 is a gene that encodes the protein KH RNA binding domain containing, signal transduction associated 1, commonly referred to as Sam68. Sam68 is a member of the STAR (Signal Transduction and Activation of RNA) family of RNA-binding proteins, which are integral to various cellular processes, including RNA metabolism, signal transduction, and cell cycle regulation. The protein is characterized by its KH domain, which is essential for its RNA-binding capabilities, allowing it to influence pre-mRNA splicing, mRNA export, and stability. Sam68 is predominantly localized in the nucleus, where it plays a pivotal role in linking signal transduction pathways to mRNA splicing, thereby affecting cell cycle progression and apoptosis. Its function is modulated by posttranslational modifications, such as tyrosine phosphorylation and arginine methylation, which impact its interactions and localization within the cell. Sam68's involvement in these processes underscores its significance in maintaining cellular integrity and homeostasis, particularly under stress conditions (Sumithra2019A; Fu2016Sam68KHDRBS1; Lukong2003Sam68).

## Structure


## Function
The KHDRBS1 gene encodes the protein Sam68, a member of the STAR family of RNA-binding proteins, which plays a crucial role in various cellular processes in healthy human cells. Sam68 is primarily involved in RNA metabolism, including pre-mRNA splicing, mRNA export, and stability. It acts as a link between signal transduction pathways and mRNA splicing, influencing cell cycle progression and apoptosis (Sumithra2019A). The protein contains a KH domain essential for its RNA-binding properties, which are critical for its function in cell proliferation and regulation of cyclin D1 expression, promoting S phase entry (Lukong2003Sam68).

Sam68 is predominantly localized in the nucleus, where it participates in nuclear-to-cytoplasmic signaling pathways, activating NF-kB in response to DNA damage. This activation is vital for the transcription of anti-apoptotic genes, helping cells survive genotoxic stress (Fu2016Sam68KHDRBS1). The protein's function is regulated by posttranslational modifications, such as tyrosine phosphorylation and arginine methylation, which affect its interactions and intracellular localization (Lukong2003Sam68). Sam68's involvement in these processes highlights its role in maintaining cellular integrity and homeostasis under stress conditions (Fu2016Sam68KHDRBS1).

## Clinical Significance
Alterations in the expression of the KHDRBS1 gene, also known as Sam68, have been implicated in various cancers. In hepatocellular carcinoma (HCC), KHDRBS1 is significantly overexpressed, correlating with aggressive tumor features such as higher tumor grades, elevated serum AFP levels, and vascular invasion. This overexpression is associated with poor prognosis and increased drug resistance, particularly to sorafenib, a common treatment for HCC (Fan2024KHDRBS1). KHDRBS1 is also linked to colon cancer, where it plays a critical role in regulating NF-kB signaling in response to DNA damage. Elevated levels of Sam68 in colon tumors are associated with increased anti-apoptotic gene expression, promoting tumor survival and progression (Fu2016Sam68KHDRBS1).

In leukemia, KHDRBS1 is involved in the post-transcriptional regulation of the MLL-AF4 fusion gene, which is crucial for controlling its oncogenic activity. Disruptions in KHDRBS1's interactions can impact the development or progression of leukemia (Okuda2022RNAbinding). Additionally, a KHDRBS1-NTRK3 fusion gene has been identified in a case of pediatric angiosarcoma, where targeted therapy with a TRK inhibitor led to complete remission, highlighting the potential of KHDRBS1 as a therapeutic target in rare cancers (Cervi2023Case).

## Interactions
KHDRBS1, also known as Sam68, is an RNA-binding protein that participates in various interactions with proteins and nucleic acids, playing a significant role in cellular processes. It interacts with the leptin receptor (LEPR) in breast cancer cells, acting as a transducer that mediates the effects of leptin on cell proliferation and growth (Maroni2020Leptin). In the cytoplasm, KHDRBS1 interacts with proteins such as Src, Grb2, and Grap, stimulating oncogenic pathways like the epidermal growth factor pathway, ERK, and Akt pathways (Maroni2020Leptin).

KHDRBS1 is also involved in the regulation of genotoxic stress-induced NF-kB activation. It interacts with PARP1, a key enzyme in PARylation, which is crucial for DNA damage response. This interaction is essential for the activation of PARP1 and subsequent PAR synthesis, facilitating NF-kB signaling (Fu2016Sam68KHDRBS1). The N-terminal region of KHDRBS1 is critical for its interaction with PARP1, and this interaction is necessary for the activation of PARP1 and subsequent PARylation (Fu2016Sam68KHDRBS1).

KHDRBS1 also forms part of a PARP1-IKKg signal complex, which is necessary for NF-kB activation in response to genotoxic stress (Fu2016Sam68KHDRBS1). These interactions highlight KHDRBS1's role in both signal transduction and RNA processing, contributing to its involvement in cancer progression and cellular stress responses.


## References


[1. (Sumithra2019A) B. Sumithra, Urmila Saxena, and Asim Bikas Das. A comprehensive study on genome-wide coexpression network of khdrbs1/sam68 reveals its cancer and patient-specific association. Scientific Reports, July 2019. URL: http://dx.doi.org/10.1038/s41598-019-47558-x, doi:10.1038/s41598-019-47558-x. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-019-47558-x)

[2. (Okuda2022RNAbinding) Hiroshi Okuda, Ryo Miyamoto, Satoshi Takahashi, Takeshi Kawamura, Juri Ichikawa, Ibuki Harada, Tomohiko Tamura, and Akihiko Yokoyama. Rna-binding proteins of khdrbs and igf2bp families control the oncogenic activity of mll-af4. Nature Communications, November 2022. URL: http://dx.doi.org/10.1038/s41467-022-34558-1, doi:10.1038/s41467-022-34558-1. This article has 10 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-022-34558-1)

[3. (Fan2024KHDRBS1) Rui Fan, Fahui Liu, Qiming Gong, Donghua Liu, Shihang Tang, and Dongyan Shen. Khdrbs1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity. Frontiers in Immunology, April 2024. URL: http://dx.doi.org/10.3389/fimmu.2024.1393801, doi:10.3389/fimmu.2024.1393801. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2024.1393801)

[4. (Fu2016Sam68KHDRBS1) Kai Fu, Xin Sun, Eric M Wier, Andrea Hodgson, Yue Liu, Cynthia L Sears, and Fengyi Wan. Sam68/khdrbs1 is critical for colon tumorigenesis by regulating genotoxic stress-induced nf-κb activation. eLife, July 2016. URL: http://dx.doi.org/10.7554/elife.15018, doi:10.7554/elife.15018. This article has 42 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.7554/elife.15018)

[5. (Lukong2003Sam68) Kiven E Lukong and Stéphane Richard. Sam68, the kh domain-containing superstar. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1653(2):73–86, December 2003. URL: http://dx.doi.org/10.1016/j.bbcan.2003.09.001, doi:10.1016/j.bbcan.2003.09.001. This article has 50 citations.](https://doi.org/10.1016/j.bbcan.2003.09.001)

[6. (Cervi2023Case) Catherine Cervi, Zoltán Sápi, Gábor Bedics, Erik Zajta, Lajos Hegyi, Judit Pápay, Katalin Dezső, Edit Varga, Katalin Mudra, Csaba Bödör, and Monika Csóka. Case report: complete and durable response to larotrectinib (trk inhibitor) in an infant diagnosed with angiosarcoma harbouring a khdrbs1-ntrk3 fusion gene. Frontiers in Oncology, February 2023. URL: http://dx.doi.org/10.3389/fonc.2023.999810, doi:10.3389/fonc.2023.999810. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2023.999810)

[7. (Maroni2020Leptin) Paola Maroni, Alessandro Luzzati, Giuseppe Perrucchini, Luca Cannavò, and Paola Bendinelli. Leptin, leptin receptor, khdrbs1 (kh rna binding domain containing, signal transduction associated 1), and adiponectin in bone metastasis from breast carcinoma: an immunohistochemical study. Biomedicines, 8(11):510, November 2020. URL: http://dx.doi.org/10.3390/biomedicines8110510, doi:10.3390/biomedicines8110510. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/biomedicines8110510)