CENP-H in Cancer: A Key Player in Tumor Progression and a Potential Therapeutic Target

Abstract

Centromere protein H (CENP-H) plays a central role in centromere function and chromosome segregation. Its overexpression in several malignancies was identified in recent research, such as renal cell carcinoma, gastric cancer, lung cancer, and breast cancer. Overexpression of CENP-H has been correlated with adverse prognosis, advanced pathological stages, and greater metastatic potential. This review discusses the pathways whereby CENP-H is involved in tumorigenesis, such as the PI3K/AKT, survivin, and mitochondrial apoptosis signaling pathways. It also addresses regulatory effects such as long non-coding RNA PVT1/miR-612 and transcription factors Sp1 and Sp3. Knowledge of how CENP-H is involved in oncogenesis can lead to new therapeutic approaches aimed at this protein, opening the door for better cancer treatment and patient prognosis.

Introduction

Centromere proteins are critical to correct chromosome segregation during cell division, and the dysregulation of these proteins is associated with aneuploidy and carcinogenesis. Among them, CENP-H has also been of notable interest because it has been aberrantly expressed in a variety of cancer types. High expression levels of CENP-H have been associated with tumor aggressiveness, poor prognosis, and therapeutic resistance. This review will summarize the function of CENP-H in cancer development, the mechanisms behind its oncogenic activity, and its therapeutic potential.

CENP-H Expression in Different Cancers

Overexpression of CENP-H has been identified in a wide range of malignancies, including but not limited to:

• Renal Cell Carcinoma: CENP-H promotes cell proliferation and is associated with higher tumor grades.

• Gastric Cancer: Patients with high CENP-H expression exhibit worse overall survival rates.

• Lung Cancer: CENP-H is linked to enhanced metastatic potential and resistance to chemotherapy.

• Breast Cancer: Elevated CENP-H levels correlate with increased tumor aggressiveness and lymph node metastasis.

• Colorectal Cancer: CENP-H plays a role in tumor progression and chemoresistance.

• Esophageal and Liver Cancers: Studies indicate that CENP-H contributes to increased tumor invasion and metastasis.

• Oral and Nasopharyngeal Cancers: Its role in these cancers further supports its function in cell cycle dysregulation.

Molecular Mechanisms of CENP-H in Cancer Progression

The oncogenic effects of CENP-H are mediated through multiple signaling pathways that regulate cell proliferation, apoptosis, and metastasis.

1. PI3K/AKT Signaling Pathway

• CENP-H upregulates the PI3K/AKT pathway, promoting cell survival and inhibiting apoptosis.

• Activation of AKT leads to increased cell proliferation and resistance to anticancer therapies.

• This signaling cascade contributes to cancer cell invasion and metastasis by regulating cellular motility.

2. Survivin Pathway

• Survivin, an inhibitor of apoptosis, is upregulated in response to CENP-H overexpression.

• This prevents cancer cell apoptosis and supports tumor growth.

• High survivin expression is associated with chemotherapy resistance and poor clinical outcomes.

3. Mitochondrial Apoptosis Pathway

• CENP-H suppresses pro-apoptotic proteins such as Bax while upregulating anti-apoptotic proteins like Bcl-2.

• This disruption of mitochondrial function leads to enhanced cancer cell survival.

• Alterations in mitochondrial dynamics due to CENP-H expression affect cancer metabolism and further promote tumor growth.

Regulation of CENP-H in Cancer

The expression of CENP-H is modulated by several regulatory mechanisms:

1. Long Non-Coding RNA PVT1/miR-612 Axis

• PVT1, an oncogenic lncRNA, enhances CENP-H expression by downregulating miR-612.

• This interaction contributes to enhanced tumor growth and metastatic capabilities.

• Experimental evidence suggests that targeting this axis could suppress CENP-H expression and reduce tumor progression.

2. Transcription Factors Sp1 and Sp3

• Sp1 and Sp3 transcription factors bind to the CENP-H promoter, increasing its expression.

• Elevated Sp1/Sp3 activity has been linked to aggressive cancer phenotypes.

• These transcription factors are also involved in drug resistance, making them potential therapeutic targets.

CENP-H as a Therapeutic Target

Given its central role in tumor progression, CENP-H presents a promising therapeutic target.

1. Small Molecule Inhibitors

• Targeting CENP-H with small molecule inhibitors may disrupt cancer cell proliferation and induce apoptosis.

• Experimental models have shown that blocking CENP-H function can significantly impair tumor growth.

2. RNA Interference (RNAi) Therapies

• Silencing CENP-H expression using RNAi-based therapies has demonstrated tumor-suppressive effects in preclinical models.

• Delivery of siRNA or shRNA targeting CENP-H could provide a new approach to cancer treatment.

3. Combination Therapy Approaches

• Inhibiting CENP-H in conjunction with chemotherapy or immune checkpoint inhibitors may enhance treatment efficacy.

• This combination approach could help overcome drug resistance and improve patient survival rates.

Potential Role of CENP-H in Cancer Diagnostics

• Biomarker for Prognosis: Elevated CENP-H levels have been correlated with disease severity, making it a useful biomarker for cancer prognosis.

• Predictive Indicator for Therapy Response: Understanding the role of CENP-H in treatment resistance can aid in developing personalized cancer therapies.

• Liquid Biopsy Applications: Emerging technologies could enable the detection of CENP-H expression in circulating tumor cells or extracellular vesicles, aiding in non-invasive cancer diagnosis.

Challenges and Future Directions

While targeting CENP-H is promising, several challenges remain:

• Selective Targeting: CENP-H is essential for normal cell division, necessitating strategies that selectively target cancer cells.

• Drug Development: Effective inhibitors need to be developed and optimized for clinical use.

• Biomarker Validation: Further research is required to validate CENP-H as a prognostic and therapeutic biomarker.

• Clinical Translation: Despite promising preclinical findings, translating these insights into effective clinical treatments requires extensive validation and large-scale clinical trials.

Conclusion

CENP-H is a new oncogenic factor involved in several cancers. As a factor contributing to tumor development, metastasis, and resistance to therapy, it is an interesting target for new cancer drugs. Future investigations should aim to design specific inhibitors that selectively hit CENP-H in cancer cells with less impact on normal tissues. Furthermore, its usefulness as a cancer biomarker for early detection and prognosis should also be investigated. Based on the expanding knowledge of its regulatory pathways, CENP-H-targeted therapies could make an important contribution to personalized cancer treatment and better outcomes. Additional studies on CENP-H-targeted therapies can offer important innovations in cancer control and better results for aggressive malignancy patients.