Literature Review on SUMOylation as a Therapeutic Target for Cancer

This literature review examines SUMOylation, a post-translational modification, as a potential therapeutic target for cancer. It details the SUMOylation pathway, its significance in cellular processes like DNA damage repair and gene expression, and its role in cancer development. The review covers studies highlighting SUMOylation's involvement in tumor angiogenesis, metastasis, and the efficacy of anti-angiogenic therapies. It also discusses the potential of targeting SUMOylation and deSUMOylation processes for cancer treatment, emphasizing the need for future research to identify small molecules that can modulate the SUMOylation pathway and contribute to novel anticancer drug development. The review concludes that SUMOylation holds promise as a biomarker and therapeutic target for cancer diagnosis and treatment.

Running head: LITERATURE REVIEW
LITERATURE REVIEW
Name of the Student:
Name of the University:
Author note:

1LITERATURE REVIEW
Introduction
The literature review conducted in this study focuses on the concept of sumolytion
and how it acts as a potential therapeutic target for cancer development. Sumoylation is
included under post-translational protein modification (PTM), which is defined as a protein
modification process and is reversible in nature1. Sumoylation is the most widely practiced
post-translational modification that takes place within the eukaryotes and is required for
maintaining genomic integrity, gene expression, intracellular signal transduction and
transcriptional regulation2. SUMOylation includes SUMO and ylation that states the small
ubiquitin-like modifier translation that will regulate different biological processes such as
DNA damage repair, carcinogenesis, apoptosis, immune response and cell cycle
development. Abnormal sumoylation result in the development of various diseases like
cancer and hence can act as a potential therapeutic target for the cancer cell3.
Literature Review
According to4, SUMOylation is the significant post-transcriptional modification
pathway that controls different cellular processes like chromosome structure, chromosome
segregation, kinetochore function, sub-nuclear and nuclear organization, DNA and
transcription damage repair.
1 Ma, J., Setton, J., Lee, N. Y., Riaz, N., & Powell, S. N. (2018). The therapeutic significance of mutational
signatures from DNA repair deficiency in cancer. Nature communications, 9(1), 3292.
2 Yang, J., Li, B., & He, Q. Y. (2018). Significance of prohibitin domain family in tumorigenesis and its
implication in cancer diagnosis and treatment. Cell death & disease, 9(6), 580
3 Chanda, A., Sarkar, A., & Bonni, S. (2018). The SUMO System and TGFβ Signaling Interplay in Regulation
of Epithelial-Mesenchymal Transition: Implications for Cancer Progression. Cancers, 10(8), 264
4 He, X., Riceberg, J., Pulukuri, S. M., Grossman, S., Shinde, V., Shah, P., ... & Bence, N. (2015).
Characterization of the loss of SUMO pathway function on cancer cells and tumor proliferation. PloS one,
10(4), e0123882.

2LITERATURE REVIEW
Source: SUMO Pathway: He et al., (2015)
The researcher conducted this study to explore the significance of SUMO pathway in
cancer cell propagation and tumor growth. Lentivirus-centred short hairpin RNAs (shRNA)
was used to knockout the genes of SUMO pathway present in the human cancerous cells. In-
vitro and In-vivo experimental study was conducted and the result demonstrated that SUMO
pathway play a crucial role in cancer cell propagation among in-vitro study and tumor growth
among in-vivo study. Hence, the researcher concluded that implication of SUMO pathway
will act as the potential therapeutic cancer target.
 Significance of SUMOylation
The significance of SUMOylation was involved in the SUMO catalytic cycle that
comprises of activation, conjugation, maturation, demodification and ligation where any
dysregulation in SUMP pathway result in various diseases primarily cancer5.
5 Gong, L., Qi, R., & W-C Li, D. (2016). Sumoylation pathway as potential therapeutic targets in cancer.
Current molecular medicine, 16(10), 900-905.

3LITERATURE REVIEW
Source: Catalytic cycle of SUMOylation: Han et al., (2018)
SUMOylation is included in DNA damage response (DDR) that controls DNA
damage recognizing and healing protein found within the nucleus. SUMOylation block or
hinder the interacting locations of various cell and substrate proteins that will affect the
protein activity by hindering protein-interaction provinces and hence produce novel docking
sites that will facilitate the interaction of protein and cell. The alteration of this protein-
interaction site will result in carcinogenesis that will upsurge the metastasis ad proliferation
of cancer6. According to7, metastasis is considered as the definitive cause that result in breast
cancer and Epithelial-mesenchymal transition (EMT) is considered to play a significant role
in developing the condition of breast cancer. SUMO E3 ligase PIAS1 is involved in the
implementation and proliferation of EMT in breast cancer metastasis and mammary epithelial
cells8. Tissue microarray analysis was done to report the protein abundance and PIAS1
6 Han, Z. J., Feng, Y. H., Gu, B. H., Li, Y. M., & Chen, H. (2018). The post-translational modification,
SUMOylation, and cancer. International journal of oncology, 52(4), 1081-1094
7 Chanda, A., Chan, A., Deng, L., Kornaga, E. N., Enwere, E. K., Morris, D. G., & Bonni, S. (2017).
Identification of the SUMO E3 ligase PIAS1 as a potential survival biomarker in breast cancer. PloS one, 12(5),
e0177639.
8 Zubiete-Franco, I., García-Rodríguez, J. L., Lopitz-Otsoa, F., Serrano-Macia, M., Simon, J., Fernández-Tussy,
P., ... & Carlevaris, O. (2019). SUMOylation regulates LKB1 localization and its oncogenic activity in liver
cancer. EBioMedicine, 40, 406-421.

4LITERATURE REVIEW
localization that is correlated with disease condition resulting in breast cancer. Hence, the
researcher concluded that SUMO E3 ligase PIAS1 is considered and used as projecting
biomarker in case of breast cancer patent thus identifying that PIAS1-SnoN sumoylation
pathway is effective in controlling the metastasis of breast cancer9.
 SUMOylation pathway
According to10, post-translational protein modification (PTM) using small ubiquitin-like
modifier (SUMO) controls the innumerable stress and homeostatic response. SUMOylation
pathway is extensively used within brain ischemia where high levels of SUMOylated protein
is proficient in persuading tolerance towards ischemic stress. Hence, SUMOylation pathway
is used as potential therapeutic target for the neuroprotection in case of brain ischemia.
According to11, any abnormalities in small ubiquitin-related modifier (SUMO) pathway and
SUMO-specific proteases (SENPs) pathway are observed in cancer were SUMOylation and
deSUMOylation are considered as the dynamic processes within cells. Hence, SUMOylation
included for cancer-related protein assist as a therapeutic biomarker used for diagnosis of
cancer and also used as a potential target considered for cancer therapy.
 Significance of SUMOylation as potential therapeutic marker
There are various studies that identify that SENPs regulate the cancer cell by mediating
apoptosis, DNA damage repair, tumor angiogenesis and cell cycle hence including their role
in tumor radio sensitivity. According to12, Slug-E-cadherin axis is considered as the crucial
9 Dworkin, A. M., Huang, T. H. M., & Toland, A. E. (2019). The role of epigenetics in breast cancer:
implications for diagnosis, prognosis, and treatment. In Pharmacogenetics of breast cancer (pp. 57-71). CRC
Press
10 Bernstock, J. D., Yang, W., Ye, D. G., Shen, Y., Pluchino, S., Lee, Y. J., ... & Paschen, W. (2018).
SUMOylation in brain ischemia: patterns, targets, and translational implications. Journal of Cerebral Blood
Flow & Metabolism, 38(1), 5-16.
11 Hu, C., & Jiang, X. (2019). The SUMO-specific protease family regulates cancer cell radiosensitivity.
Biomedicine & Pharmacotherapy, 109, 66-70.
12 Hung, P. F., Hong, T. M., Chang, C. C., Hung, C. L., Hsu, Y. L., Chang, Y. L., ... & Yang, P. C. (2019).
Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis. Journal of Experimental & Clinical
Cancer Research, 38(1), 5.

5LITERATURE REVIEW
factor in non-small-cell lung cancers (NSCLCs). The upregulation of slug stimulates cancer
metastasis. The exploration of slug protein linkage map will exhibit in detail the mechanism
of slug protein in regulation of lung cancer. Ubc9 and SUMO-1 are the slug-related protein
that were used in the study to regulate slug SUMOylation and to identify the functional
influence of SUMOylation on the slug proteins using ChIP assay, EMSA, Invasion and
reported assay and RT-PCR. Slug protein thus interact with SUMO-1 and Ubc9 that in turn
improve the transcriptional repression action of slug and therefore enhance the metastasis of
lung cancer. The researcher gave a detail insight of the EMT regulator slug modulation
through SUMOylation and unveiled novel mechanisms where SUMOylated slug encourages
cancer metastasis and invasion under hypoxia. Hence, these can be further used for the
treatment of lung cancer ad have various future implication.
 SUMOylation and deSUMOylation
According to13, small ubiquitin-related modification molecule (SUMO) is considered as
the most crucial post-translational modification (PTM) molecule that is included in diverse
cellular functions and regulates protein action and steadiness, cell cycling and transcription.
The researcher had focused that both SUMOylation and deSUMOylation are related with the
regulation of carcinogenesis within breast cancer. The role of SENPs was explained by the
researcher that exhibited that SENPs are involved in breast cancer tumorigenesis by
regulating the target protein transactivation, cell cycle, cancer cell survival and other post
translational modification. Therefore the function of SENP1 and SENP2 is used to identify
the biomarkers that will act as the potential therapeutic target for the treatment of cancer.
According to14, various studies have described that SUMOylation performs on tumor
13 Heo, K. S. (2019). Regulation of post-translational modification in breast cancer treatment. BMB reports,
52(2), 113.
14 Wang, M., & Jiang, X. (2019). The significance of SUMOylation of angiogenic factors in cancer progression.
Cancer biology & therapy, 20(2), 130-137.

6LITERATURE REVIEW
angiogenesis thereby targeting the angiogenic elements, which is considered as the crucial
post-translational modifications (PTM) step of the proteins.
 Angiogenesis
Angiogenesis is defined as the procedure of endothelial cell proliferation and migration
that is regulated by various angiogenic factors essential for tumor development. The
researcher has highlighted a novel therapy in this study named as anti-angiogenic therapy for
treatment of tumor followed by other treatments like chemotherapy and radiotherapy thereby
inhibiting the tumor growth and blocking the tumor blood vessels. Hence, it was established
from the study that SUMOylation is included as the potential therapeutic target for anti-
angiogenesis treatment. The researcher had also focused on the SUMOylation effect on
crucial signalling pathway proteins, vascular growth factors and function and migration of
endothelial cells that will deliver the updated idea of tumor treatment by using anti-
angiogenic therapy. According to15, soluble mediators and cells present within the adaptive
and innate immune system are considered as the fundamental factors under tumor
microenvironment. Various nuclear factors like cancer suppressors or oncoproteins and
transcription factors (TFs) play significant roles in regulating the cytokine function that
further leads to the growth, maintenance and cancer metastasis. It was estimated that pro-
tumorigenic surrounding are crucial for potential development and early diagnosis of targeted
cancer therapeutics thereby providing a detail insight regarding SUMOylation and
ubiquitination that post-transnationally transform the tumor suppressor TFs resulting in
progression and initiation of different cancer such as liver, breast, colorectal and prostate.
Conclusion
15 Chang, S. C., & Ding, J. L. (2018). Ubiquitination and SUMOylation in the chronic inflammatory tumor
microenvironment. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer.

7LITERATURE REVIEW
From the literature review conducted in this study highlighted the benefit of post
translational modification and how this modification will allow the detection of cancerous
target cells and therefore act as potential therapeutic target for detecting cancer. The post
translational modification was described in detail in the study and also a detail insight was
given to the authors who have contributed in the research of SUMOylation. The concept of
SUMOylation was also explained in detail and was highlighted that it is extensively used
under post-translational modification that is crucial for regulating various cellular and
biological process such as kinetochore function, DNA damage repair, chromosome structure,
nuclear organization, sub-nuclear organization, chromosome segregation and transcription
damage repair. The activity of both in-vitro and in-vivo study using SUMOylation was
explained and the mechanism of how it regulates and participates in the detection of potential
therapeutic tumor cells and cancer metastasis.
Future Directions
SUMOylation is considered as the type of post-translational modification different
SUMOylated proteins are identified but it is established that protein SUMOylation is
significant in regulating the biological activities. Hence, it is suggested that few target cells
can be modified or translated and can be used as the therapeutic target cells for identifying
the location of tumor cells and cancer metastasis16. SUMOylation and de SUMOylation
modification is used and connected with tumor progression and carcinogenesis. In the future,
various researcher can focus on the SUMOylation pathway that is crucial for developing the
clinical anti-cancer therapeutics and allowing the patient suffering from cancer to overcome
rom the condition and detect the areas of tumor progenies easily. More emphasis should be
16 Yang, Y., Xia, Z., Wang, X., Zhao, X., Sheng, Z., Ye, Y., ... & Liang, S. (2018). Small-
Molecule Inhibitors Targeting Protein SUMOylation as Novel Anticancer Compounds.
Molecular pharmacology, 94(2), 885-894.

8LITERATURE REVIEW
given on the small molecule identification that will target the SUMOylation pathway and
assist in the development of novel anticancer drug.

9LITERATURE REVIEW
References
Bernstock, J. D., Yang, W., Ye, D. G., Shen, Y., Pluchino, S., Lee, Y. J., ... & Paschen, W.
(2018). SUMOylation in brain ischemia: patterns, targets, and translational implications.
Journal of Cerebral Blood Flow & Metabolism, 38(1), 5-16.
Chanda, A., Chan, A., Deng, L., Kornaga, E. N., Enwere, E. K., Morris, D. G., & Bonni, S.
(2017). Identification of the SUMO E3 ligase PIAS1 as a potential survival biomarker in
breast cancer. PloS one, 12(5), e0177639.
Chanda, A., Sarkar, A., & Bonni, S. (2018). The SUMO System and TGFβ Signaling
Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer
Progression. Cancers, 10(8), 264.
Chang, S. C., & Ding, J. L. (2018). Ubiquitination and SUMOylation in the chronic
inflammatory tumor microenvironment. Biochimica et Biophysica Acta (BBA)-Reviews on
Cancer.
Dworkin, A. M., Huang, T. H. M., & Toland, A. E. (2019). The role of epigenetics in breast
cancer: implications for diagnosis, prognosis, and treatment. In Pharmacogenetics of breast
cancer (pp. 57-71). CRC Press.
Gong, L., Qi, R., & W-C Li, D. (2016). Sumoylation pathway as potential therapeutic targets
in cancer. Current molecular medicine, 16(10), 900-905.
Han, Z. J., Feng, Y. H., Gu, B. H., Li, Y. M., & Chen, H. (2018). The post-translational
modification, SUMOylation, and cancer. International journal of oncology, 52(4), 1081-1094
He, X., Riceberg, J., Pulukuri, S. M., Grossman, S., Shinde, V., Shah, P., ... & Bence, N.
(2015). Characterization of the loss of SUMO pathway function on cancer cells and tumor
proliferation. PloS one, 10(4), e0123882.
Heo, K. S. (2019). Regulation of post-translational modification in breast cancer treatment.
BMB reports, 52(2), 113.

10LITERATURE REVIEW
Hu, C., & Jiang, X. (2019). The SUMO-specific protease family regulates cancer cell
radiosensitivity. Biomedicine & Pharmacotherapy, 109, 66-70.
Hung, P. F., Hong, T. M., Chang, C. C., Hung, C. L., Hsu, Y. L., Chang, Y. L., ... & Yang, P.
C. (2019). Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis. Journal of
Experimental & Clinical Cancer Research, 38(1), 5.
Ma, J., Setton, J., Lee, N. Y., Riaz, N., & Powell, S. N. (2018). The therapeutic significance
of mutational signatures from DNA repair deficiency in cancer. Nature communications,
9(1), 3292.
Wang, M., & Jiang, X. (2019). The significance of SUMOylation of angiogenic factors in
cancer progression. Cancer biology & therapy, 20(2), 130-137.
Yang, J., Li, B., & He, Q. Y. (2018). Significance of prohibitin domain family in
tumorigenesis and its implication in cancer diagnosis and treatment. Cell death & disease,
9(6), 580
Yang, Y., Xia, Z., Wang, X., Zhao, X., Sheng, Z., Ye, Y., ... & Liang, S. (2018). Small-
Molecule Inhibitors Targeting Protein SUMOylation as Novel Anticancer Compounds.
Molecular pharmacology, 94(2), 885-894.
Zubiete-Franco, I., García-Rodríguez, J. L., Lopitz-Otsoa, F., Serrano-Macia, M., Simon, J.,
Fernández-Tussy, P., ... & Carlevaris, O. (2019). SUMOylation regulates LKB1 localization
and its oncogenic activity in liver cancer. EBioMedicine, 40, 406-421.